Aspectos Celulares y Moleculares Del Cáncer

Physiol Rev
83: 337376, 2003; 10.1152/physrev.00024.2002.
Clinical, Cellular, and Molecular Aspects

of Cancer Invasion
MARC MAREEL AND ANCY LEROY
Laboratory of Experimental Cancerology, Department of Radiotherapy and Nuclear Medicine,
Ghent University Hospital, Ghent, Belgium
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I. Introduction
II. Cancer Pathogenesis
III. Invasion Promoter and Suppressor Genes
A. The E-cadherin gene CDH1, an invasion/tumor suppressor
B. The N-cadherin gene CDH2, an invasion promoter
C. The E-catenin gene CTNNA1, a differentiation promoter
D. The -catenin gene CTNNB1, a tumor/invasion-promoter gene
E. Kinase and phosphatase genes, invasion promoters and invasion suppressors
F. Invasion genes and metastasis genes, separate classes?
G. Noncancer invasion-suppressor and invasion-promoter genes
IV. Cancer Cells, Host Cells, and Tumor Cells: All Invaders
A. Cancer cells and host cells
B. Myofibroblasts: stimulators of invasion
C. Angiogenesis before invasion
D. Tumor-infiltrated leukocytes: helpers of invasion
E. Osteoclasts: targets for therapy
F. Molecular cross-talk in noncancerous situations
V. Cellular Activities Associated With the Invasive Phenotype
A. Cell-cell adhesion
B. Cell-matrix interactions
C. Migration
D. Proteolysis
VI. Conclusions and Perspectives
Mareel, Marc, and Ancy Leroy. Clinical, Cellular, and Molecular Aspects of Cancer Invasion. Physiol Rev 83:
337376, 2003; 10.1152/physrev.00024.2002.Invasion causes cancer malignancy. We review recent data about
cellular and molecular mechanisms of invasion, focusing on cross-talk between the invaders and the host. Cancer
disturbs these cellular activities that maintain multicellular organisms, namely, growth, differentiation, apoptosis,
and tissue integrity. Multiple alterations in the genome of cancer cells underlie tumor development. These genetic
alterations occur in varying orders; many of them concomitantly influence invasion as well as the other cancerrelated cellular activities. Examples discussed are genes encoding elements of the cadherin/catenin complex, the
nonreceptor tyrosine kinase Src, the receptor tyrosine kinases c-Met and FGFR, the small GTPase Ras, and the dual
phosphatase PTEN. In microorganisms, invasion genes belong to the class of virulence genes. There are numerous
clinical and experimental observations showing that invasion results from the cross-talk between cancer cells and
host cells, comprising myofibroblasts, endothelial cells, and leukocytes, all of which are themselves invasive. In bone
metastases, host osteoclasts serve as targets for therapy. The molecular analysis of invasion-associated cellular
activities, namely, homotypic and heterotypic cell-cell adhesion, cell-matrix interactions and ectopic survival,
migration, and proteolysis, reveal branching signal transduction pathways with extensive networks between individual pathways. Cellular responses to invasion-stimulatory molecules such as scatter factor, chemokines, leptin,
trefoil factors, and bile acids or inhibitory factors such as platelet activating factor and thrombin depend on
activation of trimeric G proteins, phosphoinositide 3-kinase, and the Rac and Rho family of small GTPases. The role
of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of proinvasive
fragments from cell surface glycoproteins.
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0031-9333/03 $15.00 Copyright 2003 the American Physiological Society
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I. INTRODUCTION
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II. CANCER PATHOGENESIS

Cancer disturbs the cellular activities that are crucial
for the development and the maintenance of multicellular
organisms, namely, growth, differentiation, programmed
cell death, and tissue integrity. Clinically, cancer manifests itself through a tumor because of excessive growth,
through pain and bleeding because of invasion into nerves
and vessels, and through functional disturbances because
of pressure on and replacement of normal tissues. These
symptoms are not cancer specific, and the diagnosis is
made by histological examination of a sample from the
tumor. This diagnosis includes the origin and type of
cancer, its extent of growth and invasion, and its grade of
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Cancer is malignant because cancer cells invade into

neighboring tissues and survive in this ectopic site. The
term invasion indicates penetration into neighboring territories and their occupation. Cancer cells invade beyond
the constraints of the normal tissue from which they
originate; this invasion permits them to enter into the
circulation from where they can reach distant organs and
eventually form secondary tumors, called metastases. Invasion and metastasis are not unique for cancer as they
also occur during embryonic development, in healthy
adult organisms, and in many noncancerous diseases.
Ectodermal cells invade through the primitive streak and
occupy the subectodermal space where they form the
mesoderm (118, 248, 252, 399, 410). Neural crest cells
emerge from the dorsal aspect of the neural tube, migrate
to different sites in the body, and survive there to grow
and differentiate under the influence of specific local
factors (230, 400). Leukocytes leave their tissue of origin
in the bone marrow, enter into the circulation, and home
at specific sites (376). Microorganisms enter their host by
invasion through the lining epithelia of the skin or the
gastrointestinal or respiratory tracts; they eventually
reach the circulation and produce secondary lesions
(346). We have discussed previously similarities in the
molecular mechanisms of invasion by various organisms
taking as examples four families of molecules, namely,
cadherins, integrins, hydrolases, and chemokines (225).
More recently, evidence was published in favor of a role
for bacteria like Helicobacter pylori in the progression of
gastric cells toward a more invasive phenotype (170).
Noninvasive tumors are benign, because they are
cured easily by simple removal. Invasive tumors, called
cancer, invariably kill their host if untreated and, even
with optimal treatment, such tumors are a frequent cause
of death (105). In the case of primary brain tumors, such
as astrocytomas, death is due almost uniquely to local
invasion, since, for yet unknown reasons, these tumors
rarely form metastases. Cancers of the head and neck,
originating in the mucosa of the upper respiratory and
alimentary tracts, kill mainly through local invasion and
metastasis to locoregional lymph nodes. Death by colorectal cancer is due to locoregional spread in one half and
to distant metastasis in the other half of patients. In the
case of breast cancers and melanomas, death is usually
the consequence of distant metastasis. It is quite obvious
from the course of these diseases that invasion and metastasis are the hallmarks of cancer malignancy. Consequently, invasion and metastasis are major prognostic
markers. The 5-year survival rate for bladder cancer that
is limited to the epithelium is 60 80%, compared with
30 60% when invaded into the deeper muscle and 10
40% when invaded through the bladder wall into the fat,
provided radical treatment is performed. Melanoma 10-
year survival rates are 80% when the tumor invades into
the dermis but is 1.5 mm thick and 40% when it
invades into the subcutaneous fat. For primary brain tumors, the prognosis depends on the loss of differentiation
rather than on the degree of invasion. Patients with welldifferentiated astrocytomas, grade I and II, survive for 10
years or more, whereas poorly differentiated astrocytomas, grades III and IV, have a median survival of 1 year.
In infectious diseases, though they are treated much
more succesfully than malignant tumors, spread through
invasion and metastasis may also herald a bad prognosis.
In listeriosis, a disease caused by the bacterium Listeria
monocytogenes, spread from the site of entry in the intestine, to the meninges, or to the fetus in pregnant women
causes a potentially fatal disease (354). Resident noninvasive Streptococcus viridans is harmless; invasion
through wounded oral mucosa and metastasis to damaged heart valves is a cause of death in 21% of the patients
(211). Similarly, the cystic noninvasive form of Entamoeba histolytica is harmless; invasion of E. histolytica
trophozoites into the enteric mucosa causes amoebic enteritis with eventual spread to liver and brain (321).
Earlier experimental investigation of invasion and
metastasis focused on the development of appropriate
models to score invasion and invasion-related activities
by morphological techniques (1, 102, 109, 117, 164, 355,
416, 448). Today, the study of invasion benefits from the
enormous advances in genomics and proteomics, providing thousands of genes and proteins, all well characterized structurally and functionally. We review here the
more recent data about cellular and molecular mechanisms of invasion, taking selected examples with emphasis on homotypic and heterotypic cross-talk between the
invaders and the host. Noncancer invasion by normal
cells or by prokaryotic and eukaryotic cells will be discussed for comparison with cancer invasion. For a review
of the older literature, the reader is referred to Reference
249. A selected literature search for the present review
was closed in November 2001.
CANCER INVASION
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noma in situ. There has been a long debate about whether

a common initiated progenitor cell population would give
rise to both noninvasive and invasive lesions (field theory)
or a noninvasive precursor lesion would transit toward
invasive lesions (progression theory). In favor of the progression theory is the concept that somatic mutations
favoring continuous proliferation or low apoptosis led to
clonal expansion and to continuous selection of progressively more malignant cell populations (334). Moreover,
at least part of the genetic abnormalities of invasive cancers are also found in apparently normal and in preinvasive lesions, as exemplified in the breast (101), the prostate (100), the esophagus (199), and the bronchus (57).
The scenario inferred from these clinical observations is
confirmed in models of experimental carcinogenesis in
the rat colon and in the mouse skin (384, 454).
The above-mentioned clinical and experimental observations indicate that cancer is a disease of growth,
causing accumulation of cells, of differentiation, causing
loss of structure and function, and of tissue organization,
leading to invasion and survival in an ectopic environment (Fig. 1). A multistep process of invasion leads to
metastasis: invasion from the tissue, in which the cancer
has originated, into the surrounding tissues through barriers such as the epithelial basement membrane; entry
into blood or lymph vessels; transport through the circulation; arrest and exit from the circulation at the putative
site of metastasis; and invasion into the tissues of the
occupied organ. Although cancer is generally thought to
evolve from bad to worse, large variations in the rate of
progression have been published. In a number of studies
collected from the literature about patients with cervical
lesions that remained untreated against advice but accepted follow up, progression from carcinoma in situ
toward invasive carcinoma varied between 3 and 70%
(71). For earlier stages of cancer development, the probability of progression is lower than for more advanced
stages of the disease, as suggested in Barretts esophagus
(162). Such differences in progression between earlier
and later stages of cancer development suggest a point of
no return where precursor lesions transit into lesions that
in most cases progress toward invasive cancer. This is
certainly the case for most cancers that have reached the
stage of invasion and metastasis. There are, nevertheless,
observations indicating that reversion to a more normal
stage of at least part of the cancer cell population is
possible. Regression of metastasis from hypernephroma
upon removal of the primary cancer without adjuvant
therapy has been described but remains a rare event with
an unknown biological mechanism (105). Metastases
sometimes show a higher degree of differentiation and
grow with less or no invasion compared with the primary
cancer. This suggests that the progression model should
not assume that invasion and metastasis-associated phenotypes are fixed by genetic alteration. Colorectal carci-
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differentiation. Attention is paid also to the host cell

reaction evidenced by the stroma, blood vessels, and
leukocytes. Because cancers are known to metastasize,
the physician will search for secondary tumors in the
lymph nodes and in distant organs. Growth, at least to the
minimum volume detectable by the actual diagnostic
techniques, is a prerequisite to find secondary tumors.
Qualitative and quantitative criteria are used to stage and
grade cancers for therapeutic and prognostic purposes.
Staging of tumors is done following the volume of the
primary tumor and its depth of invasion (T stage), the
number and the volume of occupied lymph nodes as well
as invasion through their capsula (N stage), and the presence of distant metastases (M stage). This TNM system,
propagated by the International Union Against Cancer, is
widely used in Europe (372). For example, a T4, N1biii,
M1 breast cancer has invaded into the skin, occupied
axillary lymph nodes with invasion through their capsula,
and has metastasized to distant organs such as bone, liver,
brain, or lungs. A T2, N0, M0 breast cancer has a diameter
not exceeding 5 cm and no metastasis are detected.
Kaplan-Meyer survival curves show that patients with
such T2 cancers, provided accurate treatment is given,
have 70% chances of being alive 5 years after diagnosis.
Attempts are made to refine staging by the identification
at diagnosis of these 30% of cancers that are not controlled by this treatment. The actual efforts include the
search for micrometastases that are not detected in the
routine TNM system. Immunohistochemistry, with antibodies against epithelial marker proteins, of lymph nodes
and bone marrow in breast cancers that were scored N0,
M0 by the standard criteria showed immunopositive cells
in the lymph nodes in 6.4%, in the bone marrow in 26.0%,
and in both in 4.8% of the patients (144). It is tempting to
speculate that the presence of such micrometastases
might predict the above-mentioned 30% of lethal cases.
One decade of careful follow up is, however, needed to
know the answer to the crucial question whether or not
such nests of cancer cells will survive, grow, reach clinically relevant volumes, spread to other organs, and eventually kill their host. Grading is based on the loss of
differentiation, sometimes combined with mitotic activity. Individual cancers are currently portrayed by DNA,
RNA, and protein microarray systems, covering as many
characteristics of maligancy as possible. Whether or not
this method will enter into clinical routine for staging and
grading is an open question (194).
Noninvasive precursor lesions, i.e., histological abnormalities in which cancer is more likely to occur than in
the normal tissue counterpart, are found in the vicinity of
invasive cancers (71, 135). There is compelling evidence
to accept that many types of cancers have benign precursor lesions, recognized by accumulation of cells, such as
in hyperplasia and adenoma, or by loss of differentiation
and nuclear abnormalities, such as in atypia and carci-
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FIG. 1. Schematic representation of genetic,

epigenetic, and phenotypic aspects of cancer development. [Adapted from Mareel and Bracke
(247).]
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after, invade and metastasize as nondividing cells. Parasitic trypanosomes and leishmania pass through an obligatory nondividing stage when they invade from one host
into another or from one tissue into another (279).
III. INVASION PROMOTER AND
SUPPRESSOR GENES
A series of alterations in the genome of the cell population of origin forms the basis of tumor development (40,
130). The genes of interest are classified as oncogenes or
tumor-promoter genes, one allele of which is activated leading to gain-of-function events, and tumor-suppressor genes
or antioncogenes, both alleles of which are inactivated leading to loss-of-function events. Genomic instability, due either
to impairement in DNA repair (microsatellite instability) or
to dominant negative mutations in mitotic check-point genes
(chromosomal instability), leads to activation of oncogenes
and inactivation of tumor suppressor genes. The products of
these genes belong to various classes of protein families,
such as cytokines, cell surface receptors, signal transducers,
and transcription factors. The list of oncogenes encoding
cell surface receptors of the protein-tyrosine kinase family
alone counts more than 40 members (42). Mechanisms of
activation of oncogenes implicate mutation, gene amplification, and promoter activation. Mechanisms of tumor-suppressor inactivation are exemplified by loss of heterozygosity (LOH) plus silencing of the second allele genetically,
through mutation, or epigenetically, through methylation. In
familial cancers, one mutation is carried with the germline.
Well-documented examples include RB in retinoblastoma,
BRCA1 in breast cancer, and adenomatous polyposis coli
(APC) in colon cancer of the familial adenomatous polyposis (FAP) type. Cancer-related genetic alteration are multiple
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noma metastases may resemble the organized epithelial

and tubular structure of a well-differentiated primary cancer, whereas the invasive front of the actual primary
cancer displays loss of the epithelioid morphotype and
appearance of fibroblastoid, presumably invasive and
metastatic, cancer cells. An experimental demonstration
is provided by cocultures of human colon cancer cells
with enteric lymphoid cells, in which the cancer cells
transit to M cells, a differentiated type of absorptive enterocytes covering Peyers patches (208).
There are indications that abnormal growth and invasion are not necessarily associated during cancer development. Metastasis without primary tumor, called CUP
for cancer with unknown primary, is not a rare event
(510% of all cancer patients with metastases). In such
cases, the primary tumor cannot be found at the time of
clinically evident, hence growing, metastases. Primary
tumors may appear later or not at all. Conversely, metastases may grow to reach clinically relevant volumes many
years after removal of the primary cancer as exemplified
by ocular melanoma. Both clinical observations indicate
that invasion and growth at the primary or secondary site
can be regulated independently, a conclusion that is confirmed by the experimental finding that pharmacological
agents can arrest growth whilst permitting invasion, and
vice versa (385). This growth-separate-from-invasion concept deals probably with the exception; in the majority of
invasive cancers, a complex and probably coordinated
program of invasion, growth, survival, and loss of differentiation is at the basis of the clinical manifestations of
the disease. It is, indeed, logical to accept that proliferation is needed to provide a cohort of invaders and that
inhibition of apoptosis keeps them alive in an ectopic
matrix environment. Considering noncancer invasion,
leukocytes do proliferate in the bone marrow and, there-
CANCER INVASION
A. The E-cadherin Gene CDH1,

an Invasion/Tumor Suppressor
Epithelial (E)-cadherin is a transmembrane glycoprotein of the type I cadherin superfamily (299); its cytoplasmic part is linked to the actin cytoskeleton via the
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catenins, -catenin, -catenin, and plakoglobin (-catenin). The gene encoding E-cadherin (CDH1, on chromosome 16q22.1) was one of the first to be considered as an
invasion-suppressor gene (30, 138, 432). The experimental
strategy consisted of the isolation from heterogeneous
cell lines of clones with an epithelioid (e-type, resembling
epithelial cells) morphotype and a fibroblastic (f-type,
resembling fibroblasts) morphotype. The e-type cells
were E-cadherin positive, failed to invade into organotypically cultured embryonic chick heart, and formed a differentiated epithelial layer around the heart tissue. The
f-type cells were E-cadherin negative, did invade, and
showed no epithelial differentiation. Similarly, a positive
correlation was found between the invasion into collagen
type I of human cancer cell lines and the lack of Ecadherin. The invasive phenotype as well as the morphotype of these cells could be manipulated in both directions, from e-type noninvasive to f-type invasive, and vice
versa, by transfection with sense or antisense E-cadherin
cDNA. The e- to f-type conversion is reminiscent of the
epithelial to mesenchymal transition (coined EMT) observed during gastrulation. Interestingly, loss of E-cadherin in immortalized cell lines of noncancerous origin
did induce the invasive phenotype, only when the cells
were transfected with an oncogene (Fig. 2). Conclusions
from these experimental findings were confirmed by immunohistochemical changes in E-cadherin expression
and localization in most human cancers (56, 92, 98, 275,
276, 305, 353, 366, 419, 421). The positive correlation
between cancer aggressiveness as evidenced by poor survival and disturbance of E-cadherin provides clinical support for E-cadherin as an invasion suppressor (304). Such
clinical evidence is, however, at best circumstantial since
deficient expression of E-cadherin may also be due to
posttranscriptional and posttranslational events. The
causal relationship between E-cadherin expression and
invasion in vivo was convincingly demonstrated in transgenic mice (319). Such mice, expressing the tumorigenic
simian virus 40 (SV40) T antigen under the insulin promoter (Rip1Tag), developed pancreatic -cell adenomas
in 74% and invasive adenocarcinomas in 26% of the mice.
Overexpression of E-cadherin under the same promoter
(Rip1E-cad) did not cause tumors. Rip1Tag Rip1E-cad
crosses had a lower (8%) ratio of adenocarcinomas, showing that overexpression of E-cadherin counteracted the
acquisition of the invasive phenotype. In contrast, crosses
of Rip1Tag mice with mice expressing dominant negative
E-cadherin that lacks the extracellular domain (Rip1dnEcad) had invasive and metastatic carcinomas in 50% of the
cases.
Mutations in CDH1 are the exception rather than the
rule as they occur only in diffuse type gastric cancer,
lobular breast cancer, and endometrial cancer (2527, 35,
36, 196). In invasive lobular breast cancers, a subtype in
which cancer cells invade as Indian files, total loss of
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and occur in varying orders so that it is difficult to ascribe

defined genetic alterations to distinct stages of tumor development (18, 77, 456). The sequence of genomic alterations
during tumor development might be of particular interest for
the understanding of their role in the acquisition of invasion.
Are the genes implicated in invasion different from those
implicated in growth disturbance, loss of differentiation, and
of sensitivity to death signals? The recognition of some stage
specificity of genetic alterations has led us previously to
believe that oncogenes and tumor-suppressor genes were
implicated in growth disturbance and that they differed from
genes promoting or suppressing differentiation, invasion, or
survival (250). The growing list of cancer genes, however,
comprises several examples of oncogenes and tumor-suppressor genes that are, either in the same or in different
types of tumors, implicated in earlier stages of growth disturbance as well as in the later stages when invasiveness is
acquired (27). Furthermore, the categorization of tumor phenotypes in growth, differentiation, survival, and invasion
underestimates the mutual relationships between these phenotypes (125). To illustrate, growth is the basis for clonal
expansion of somatic cells, differentiation and proliferation
are inversely related, and survival signals are implicated in
invasion because normal cells die inside foreign trophic
microecosystems (358). The known function of the gene
product, sometimes, makes the stage of appearance of the
genetic alteration unexpected. Loss of p53, the guardian of
the genome, is frequently found at the transition between
the noninvasive, premalignant and the invasive, potentially
malignant stage, and this is later than expected from the
more general role of the p53 phosphoprotein functioning in
the check-point control that arrests cells with damaged
DNA. In line with this observation, p53 null mice are less
susceptible to induction of papillomas, but once the papillomas arise, they transit rapidly to carcinomas. The effect of
gene activation may depend on the stage of development at
which it occurs. For example, transforming growth factor-
(TGF-) acts as a tumor suppressor in early stages of tumor
development, whereas it causes invasion and metastasis
upon inducible transgenic expression in papillomas (439).
The following discussion about invasion-suppressor and invasion-promoter genes and their alterations during tumor
development chooses examples on the basis of the interest
of the authors laboratory. The more tumor-suppressor or
-promoter genes are examined, the better it is realized that
many of them affect invasion as well as growth and differentiation.
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FIG. 2. E-cadherin promoter with

positive and negative transcriptional regulators. For detailed description, see section IIIA. [Adapted from Van Aken et al.
(419).]
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sition of an e-morphotype, and loss of invasiveness. The

host mouse context responsible for the changes in Ecadherin expression has, not yet, been identified. Reversible downmodulation of E-cadherin is suggested also by
its reexpression in metastases from breast cancers (63).
Similar observations with colorectal cancers led to the
conclusion that, to grow at the metastatic site, disseminated f-type cancer cells must regain at least some of their
epithelial functions (53).
Methylation of DNA is a common type of transcriptional modification in mammals. It normally occurs during
genomic imprinting and X chromosome inactivation.
Highly methylated DNA is found in genetically silent regions of chromosomes, and hypermethylation of CpG islands in the promoter region of a gene leads to transcriptional silencing. This mechanism of downregulation was
observed in several tumor-suppressor genes such as APC,
von Hippel-Lindau (VHL), RB, and also CDH1 (124).
Germline mutations in CDH1 without loss of heterozygosity at the CDH1 locus are suggestive for hypermethylation. In hereditary diffuse gastric cancer, with a mutation
in one CDH1 allele, hypermethylation constitutes the second hit eliminating the expression of E-cadherin (155). In
this type of cancer and also in esophageal cancer, hypermethylation may occur as early as the intramucosal, i.e.,
noninvasive stage, of the disease, underscoring the tumorsuppressor function of E-cadherin (116, 391). In a gastric
cancer cell line, the expression of E-cadherin could be
restored by treatment with the demethylating agent 5-azacytidine. Some authors have cautioned interpreting hypermethylation in terms of tumor development, as they
consider that the causal relationship between both phenomena is not firmly established (129).
The promoter of CDH1 contains positive regulatory
elements, a CCAAT-box and GC-boxes, as well as two
E-boxes (29, 150). Proteins acting directly or indirectly on
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E-cadherin expression is due to E-cadherin gene mutations combined with loss of the wild-type allele. The
above-mentioned observations are compatible with inactivation of CDH1 either at the transition between the
noninvasive to the invasive stage or earlier. In lobular
breast cancer early inactivation of CDH1 was demonstrated, putting forward CDH1 also as a tumor-suppressor
gene (435). The same truncating mutations associated
with loss of heterozygosity were found in sporadic lobular
carcinoma in situ as in the associated invasive components but not in atypical hyperplasia. In diffuse type gastric cancers, the amplification product of E-cadherin
cDNA was shorter than the expected 630 bp due to skipping of exon 9 or 8. In favor of the tumor-suppressor
function of the E-cadherin gene is the finding of inactivating germ line mutations in families with a higher incidence of diffuse gastric cancer. Interestingly, the mother
of one of the gastric cancer patients suffered from metachronous lobular breast cancer and diffuse gastric cancer
and had the same CDH1 germline mutation as her child
(206).
The low frequency of E-cadherin mutations is in
striking contrast to the almost ubiquitous disturbance of
E-cadherin in invasive and even in preinvasive cancers,
suggesting other mechanisms of transcriptional or posttranscriptional downregulation. Such forms of downregulation may be reversible. In an experimental tumor model
with an immortalized normal kidney-derived epithelial
cell line Madin-Darby canine kidney (MDCK) transformed
by a mutated RAS oncogene and coined MDCK-ras, Ecadherin-positive variants had an e-morphotype and were
noninvasive in vitro, but produced invasive and metastatic cancers after injection into nude mice (246). Immunohistochemistry of the nude mouse tumors revealed loss
of E-cadherin, but ex vivo culture of the MDCK-ras tumors resulted in rapid reexpression of E-cadherin, acqui-
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colon cancer HCT-8 cells, coined HCT-8/E11 for clonal

selection of an epithelioid morphotype, they induce the
invasive phenotype, and invasion is enhanced by addition
of TGF- to the culture medium through an, as yet, unknown mechanism (328). In cells from the normal murine
mammary gland (NMuMG) family (273) and in pancreatic
cancer cells carrying an activating RAS mutation (121),
TGF- caused an e- to f-morphotype transition and invasion, with downregulation of E-cadherin and of other
junctional proteins.
B. The N-cadherin Gene CDH2,
an Invasion Promoter
Gain of N-cadherin in cancer cells accompanies loss
of E-cadherin, acquisition of an f-morphotype, increased
motility, and invasion both in vitro and in vivo as summarized in Reference 419. In some of these cancer cells, Eand N-cadherin are coexpressed. In such cells, the invasion-promoter potency of N-cadherin seems to dominate
the invasion-suppressor potency of E-cadherin. Indeed,
N-cadherin promotes invasion and motility of human
breast cancer cells in a way that is not overcome by
forced expression of E-cadherin (290, 291). A weakly
metastatic E-cadherin expressing breast cancer cell-line
of the MCF-7 family, yielded, upon successful transfection
with N-cadherin, cells that coexpressed E- and N-cadherin
and that were highly metastatic (167). Conversely, Ecadherin transfection in N-cadherin expressing breast
cancer cells did not revert their invasive phenotype. The
shifts from E-cadherin to N-cadherin raise the question
whether the expression of both genes is coregulated.
Transfection experiments yielded conflicting results. Decreased N-cadherin expression upon transfection with
cDNA encoding L-CAM, the chicken homolog of E-cadherin, was ascribed to instability of the N-cadherin protein and not to reduced transcription (234). In squamous
carcinoma cells, transfection of N-cadherin cDNA caused
a decrease in E-cadherin expression; conversely, when
N-cadherin expression was decreased by antisense transfection, E-cadherin expression increased (182). That repressors of E-cadherin may transactivate the gene encoding N-cadherin is demonstrated for the zinc finger protein
Snail (21, 68). The retinal pigment epithelium (RPE) of the
human eye may provide an interesting experimental
model for the further analysis of the E- to N-cadherin shift
(64; E. Van Aken, personal communication). In the eye,
the RPE expresses mainly E-cadherin; shortly after explantation in vitro, RPE cultures show a majority of Ecadherin-negative, N-cadherin-positive cells with an fmorphotype. When such RPE cells are seeded on collagen
gel, they extensively invade, and invasion can be blocked
by addition of the N-cadherin neutralizing antibody GC-4.
Clinical data do not substantiate unanimously the inva-
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the E-cadherin promoter are presented in Figure 2. Note

that some of these proteins are encoded by genes that
were classified as tumor-suppressor genes or as protooncogenes. In MDCK cells, coined MDCK(LT), the SV40
large-T antigen, encoded by a viral oncogene, inactivates
RB and causes a transition from the e- to the f-morphotype that is associated with loss of epithelial markers,
including E-cadherin, and with loss of expression of the
oncogene MYC (258). The latter encodes two distinct Myc
proteins, acting as transcription factor (22). Transfections
of dog kidney MDCK and human skin HaCat cells show
that RB and Myc specifically activate transcription of the
E-cadherin promoter, a phenomenon that is mediated by
the transcription factor AP-2 (23). Transactivation of the
E-cadherin promoter is strongly dependent on the expression ratio between the two Myc proteins and is cell type
specific. The finding that inactivation of RB by human
papilloma virus HPV16E7 in primary human mammary
epithelial tissue explanted in reconstituted extracellular
matrix does not interfere with the correct expression of
E-cadherin confirms this cell type specificity (374). In
such cultures, viral inactivation of RB causes loss of the
differentiation markers lactoferrin and cytokeratin-19.
These experiments illustrate the complexity of oncogenic
pathways: a viral tumor-promoter binds to and inactivates
a cellular tumor-suppressor that indirectly counteracts
invasion in one type of cells and maintains differentiation
in another type. The Wilms tumor 1 (WT1) may transactivate CDH1 directly through binding to the proximal
GC-rich sequence in the promoter as evidenced by transfection of 3T3 fibroblasts (174). Snail, a member of a
multi-zinc finger protein family of transcription factors, is
a strong repressor of CDH1, interacting specifically with
E-boxes in the E-cadherin promoter and, so, repressing
transcription of CDH1; in this way, it causes an e- to
f-morphotype transition and invasion (21, 68). Snail is
expressed in fibroblasts, in some E-cadherin-deficient cell
lines, and in invasive regions of experimental carcinomas.
Smad interacting protein 1 (SIP1) belongs to the same
zinc finger protein family as Snail and displays specific
DNA binding activity (81). It interacts with several members of the Smad protein family. Conditional expression
of SIP1 in MDCK-Tetoff cells, an MDCK-derivative stably
expressing the Tetoff transactivator, abrogates the expression of E-cadherin and of cell-cell adhesion as well as
unidirectional migration that are both sensitive to inhibition by E-cadherin-neutralizing antibodies; it simultaneously induces invasion into collagen gels. Members of
the Smad protein family, which normally act in the TGF-
signaling pathway cooperatively with other transcription
factors (104, 450), are implicated in invasion in, yet, another way. SMAD2 genes with a mutation of Ser at position 465 are found in colon cancer and in lung cancer.
When such genes, encoding an unphosphorylable form of
Smad2, are transfected into MDCK cells or into human
343
344
sion promoter role of N-cadherin. Immunohistochemical

analysis of 75 bladder cancers led to the conclusion that
focal expression of N-cadherin in urothelial cancers is a
frequent phenomenon, but its significance for invasion is
unclear (335).
C. The E-catenin Gene CTNNA1,
a Differentiation Promoter
Physiol Rev VOL
D. The -catenin Gene CTNNB1,

a Tumor/Invasion-Promoter Gene
-Catenin, like the other catenins, was described first

as an essential element of the E-cadherin/catenin complex (311). In normal cells, -catenin is associated not
only with cadherins but also with the APC multiprotein
complex (157). Here, it is phosphorylated by the serine/
threonine kinase glycogen synthase kinase (GSK)-3 and
directed to the ubiquitine proteasome pathway for degradation (see Fig. 8). The APC complex belongs to the Wnt
signaling pathway, in the context of which -catenin may
act as a tumor promoter (32, 341, 387, 446). Mutations in
the serine/threonine phosphorylation sites of -catenin
make it resistant to degradation. After saturation of the
E-cadherin complex, the superfluous -catenin stays in
the nucleus in association with lymphocyte enhancer factor (LEF)/T-cell factor (TCF) influencing transcription.
Because TCF proteins possess no intrinsic ability to modulate transciption, coactivators such as the acetyltransferases p300 (169), Smad3 (220), and Pontin52 (24) are
crucial. In contrast, Reptin52 (repressing pontin52) acts
as a repressor. An overview of -catenin mutations in
human tumors is listed in Reference 298. This list contains
desmoid tumors, locally invasive outgrowths of mesenchymal cells that do not produce metastases (398).
-Catenin mutations are limited to certain types of cancer; they are not found in squamous cell carcinomas of
head and neck and esophagus, gastric carcinomas, or
lobular and ductal breast carcinomas (67, 99, 153). In a
series of 58 colorectal cancers without APC mutation,
there were no CTNNB1 point mutations, but 7 tumors
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-Catenins are considered to be essential elements of

the E-cadherin invasion suppressor complex (173, 415).
The CTNNA1 gene encoding E-catenin is localized on
chromosome 5q3.1 (300). In cultures of the human colon
cancer clone HCT-8/E11, round cells (r-morphotype) can
be observed either on top of the epithelioid (e-type) cell
layer or floating in the culture medium (429, 431). Examination of the E-cadherin/catenin complex in harvested or
cloned r-type cells showed that loss of E-catenin caused
the transition from an e- to r-morphotype in an irreversible manner. Repeated screening of a series of colon
cancer cell lines stored in our and in other laboratories as
well as purchased from commercial stock, showed a similar morphotypic instability with spontaneous emergence
of similar r-type variants in routine culture as observed
with HCT-8/E11. DNA fingerprinting of cell lines coined
HRT-18, DLD-1, or HCT-15 all had the same microsatellite
instability DNA profile as HCT-8, strongly indicating that
they all originated from the same patient (430). Such
confusion about the identity of cell lines kept in various
deposits was recently estimated to be 36% (262). In the
case of the HCT-8 family, the confusion was useful because it pointed toward a genetic background for the e- to
r-type transition as it occurred in all the cell lines that had
the same DNA profile. Cells of the HCT-8 family carry a
heterozygous mutation in a CTNNA1 gene and mutation
or loss of the remaining wild-type allele causes loss of
-catenin and the above-mentioned e- to r-morphotype
transition. CTNNA1 is, therefore, considered as a tumorsuppressor gene in accordance with Knudsons criteria
(213). The conclusion about the cellular activity suppressed by E-catenin depended on the assay used to test
the cells. In the chick heart invasion assay (Fig. 3), Ecatenin-positive e-type HCT-8/E11 cells are not or poorly
invasive with a few undifferentiated cells inside the peripheral rim of the heart tissue, in contrast to the Ecatenin-negative r-type cells that massively occupy the
heart tissue without any sign of differentiation. These
experiments led to the conclusion that CTNNA1 is an
invasion-suppressor gene (429). However, differentiation
constituted another striking difference between the two
cell types. When assayed on top of collagen type I gels,
both types of cells fail to invade unless cancer-associated
myofibroblasts are admixed to the collagen (106). In the
presence of myofibroblasts, both e- and r-type cells do
invade, the former as epithelioid strands and the latter as

loose files of undifferentiated cells. It is, therefore, justified to consider CTNNA1 as a differentiation gene, influencing invasion only in a quantitative way and, possibly,
as a consequence of changes in differentiation. When
injected orthotopically into the wall of the cecum of nude
mice, genotypic differences in CTNNA1 between e- and
r-type cells were conserved, but phenotypic differences
could not be seen any more; both variants produced
moderately differentiated invasive adenocarcinomas that
were undistinguishable from one another (426). Reexpression of -catenin in an E-cadherin-positive prostate
cancer cell line PC-3 suppressed tumorigenicity in nude
mice (127), suggesting a role for -catenin in ectopic
survival. Recent data suggest that E-catenin not only
functions through maintainance of cell-cell adhesion but
also through interference with -catenin/Tcf/DNA complex formation and -catenin signaling in the nucleus
(147). The above-mentioned data again illustrate the implication of a single gene in multiple tumor progressionassociated phenotypes.
CANCER INVASION
345
FIG. 3. In vitro assays for invasion of cancer cells and of bacteria. For further details about these and other assays
for cancer cell invasion, see Ref. 61; for the bacterial invasion assay, see Ref. 349.
showed deletions of 234 760 bp, each of which included

all or part of exon 3 (184). Retention of -catenin in the
nucleus may result also from mutations in the -catenin
binding site of APC, which is necessary for the formation
of the complex in which GSK-3-mediated phosphorylation occurs (283). Mutation in the armadillo repeats is one
of the oncogenic changes in APC, a tumor suppressor that
is implicated in sporadic and familial colon cancer (326),
as evidenced also in transgenic mice (133). The participation of APC at tumor development is probably not limited
to growth, as the APC proteome also regulates morphogenesis (19). Target genes of the -catenin/TCF transactivator complex comprise the genes encoding matrix metalloproteinase-7 (MMP-7; matrilysin) (90), myc (168),
cyclin D1 (236), multidrug resistance protein 1 (MDR1)
(453), two components of the AP-1 transcription complex
jun and fra-1 (245), and the putative transcriptional regulator AF17 (237). In melanoma cells, the acquisition of the
TGF--dependent fibroblastic morphotype is accompaPhysiol Rev VOL
nied by localization of -CTN in the nucleus and an increased expression of MMP-9, next to an increase of
integrin-linked kinase (ILK), 1- and 3-integrins, and a
decrease of E-cadherin (186). We would like to emphasize, here, that an element of an invasion-suppressor complex transactivates genes that are implicated not only in
the modulation of growth, differentiation and response to
therapy, but also in the stimulation of invasion and invasion-associated cellular activities. In cancers where mutations in -catenin, APC or conductin (equal to axin) (28)
are uncommon, -catenin may be upregulated by the
prolyl isomerase (Pin1) resulting in the transcription of
several -catenin target genes (344). Pin1 interferes with
-CTN/APC interaction by changing the conformation of
the phosphorylated Ser/Thr-Pro bonds. There is less evidence in favor of CTNNB1 as an invasion-suppressor
gene. An in-frame deletion in the E-catenin binding site
of -catenin in a signet ring cell carcinoma cell line (HSC39) causes disruption of the cadherin-dependent cell-cell
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346
E. Kinases and Phosphatase Genes, Invasion

Promoters and Invasion Suppressors
Phosphorylation and dephosphorylation are key phenomena in intracellular signaling, and genes encoding
kinases and phosphatases are on the list of oncogenes and
tumor-suppressor genes. We discuss their putative roles
in invasion, taking the examples of the nonreceptor tyrosine kinase SRC, the receptor tyrosine kinases c-MET
and FGFR, the small GTPase RAS and the dual phosphatase PTEN. Doubtless, many more genes encoding other
members of these protein families may act as invasion
promoters or invasion suppressors (see list in Ref. 42).
1. Src
SRC is the first oncogene detected (381) and a prototype showing many characteristics of the other oncogenes (259). The viral oncogene v-SRC has a cellular
counterpart c-SRC that is activated by mutation to bePhysiol Rev VOL
come an oncogene. Such activating mutations are found

in human cancer both in early and late stages of development (72, 180). In some colorectal cancers, SRC activation, through truncating mutations in a critical carboxyterminal tyrosine, probably has a role in malignant
progression (180), supporting its invasion-promoter function. The Src protein is anchored to the plasma membrane
through myristoylation, receives various signals, signals
in its turn to many substrates directly and indirectly (see
Fig. 11), and is implicated in numerous cellular functions,
including proliferation, motility, as well as cell-cell and
cell-substrate adhesion (402). Temperature-sensitive mutants of SRC were used to transform MDCK cells, the
invasion of which into embryonic chick heart or into
collagen gels could be switched on by changing the incubation temperature from 39.5 to 35C (31). In these MDCKts.src cells, activation of Src leads to loss of E-cadherin
functions, as evidenced by deficient cellular aggregation
and gain of invasion. One of the molecular changes of
interest in the E-cadherin/catenin complex is tyrosine
phosphorylation of -catenin, weakening its binding with
E-cadherin. In PC/AA/C1 cells, derived from a colon polyp
in a FAP patient, introduction of activated SRC was not
sufficient to induce invasion, but made the cells sensitive
to stimulation of invasion by other factors (123). Indeed,
the parental cells (PC/AA/C1) failed to invade into collagen in vitro, even after stimulation with scatter factor
(SF)/hepatocyte growth factor (HGF), whereas their SRCtransfected derivatives (PCmsrc) did invade upon addition of SF/HGF. The membrane-associated polyoma middle T oncoprotein (py-MT), known to increase the
tyrosine kinase activity of pp60c-src by preventing phosphorylation of Y527, mimicked some of the transforming
effects of SRC but not its proinvasive activity (294). In rat
bladder cells NBT-II, Src activity correlates with loss of
epithelial differentiation and metastasis (51). During gastrulation movements in the Xenopus embryo, Src kinases
are pivotal as evidenced by in vivo injection of mRNAs
coding for dominant negative forms of ubiquitous members of the Src family.
2. Receptor tyrosine kinases
The activation of receptor tyrosine kinases, such as
c-Met and FGFR, contributes to invasion. The c-Met receptor for SF/HGF consists of a 50-kDa extracellular
-subunit that is disulfide-linked to a 145-kDa -subunit
having cytoplasmic tyrosine kinase domains and sites of
tyrosine phosphorylation (48, 286). The effects of SF/HGF
on motility, invasion, and proliferation are due to activation of the c-Met receptor as shown by transfection of
hybrid cDNA encoding the ligand binding domain of nerve
growth factor and the transmembrane and tyrosine kinase
domains of c-Met (442). Mutation and overexpression of
c-Met are associated with tumor progression in various
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adhesion (196, 201, 310). In normal mesenchymal cells

and in uveal melanoma, cytoplasmic nonphosphorylated
-catenin might well participate at invasion without translocating into the nucleus (210).
Plakoglobin, also called -catenin, is a close homolog
of -catenin, sharing the 12 armadillo repeats; both may
promote tumor formation when overexpressed (17). In
adherens junctions, these two molecules bind independently to E-cadherin, and plakoglobin binds also to the
desmosomal cadherins desmoglein and desmocollin. Unlike for -catenin, neoplastic transformation by plakoglobin does not implicate stabilizing mutations (215). It does,
however, require transcriptional activation of the oncogene MYC via plakoglobin/TCF complexes. One possible
difference between the two armadillo proteins may be the
type of binding coactivator proteins as suggested by differences in their carboxy-terminal parts. In experimental
systems, plakoglobin may also act as a tumor suppressor
and as a tumor promoter (458). Overexpression of plakoglobin in cells from a human tongue squamous cell carcinoma SCC9 causes uncontrolled growth and inhibition of
apoptosis. Here, plakoglobin exerts a growth regulatory
function by induction of the antiapoptotic protein BCL-2,
independently of its role in mediating cell-cell adhesion
(160). In the above-mentioned observations of metastatic
breast cancer by Bukholm et al. (63), most members of
the E-cadherin/catenin complex, including -catenin,
were reexpressed in the metastases, whereas plakoglobin
was lost. Mutation of APC, as frequently observed in
colon cancer, results in elevated levels of both -catenin
and plakoglobin (216, 283). Taken together, plakoglobin
and -catenin are best considered as separate players in
tumor development with close links to each other as well as
to other elements of the cadherin and the APC complexes.
CANCER INVASION
3. Ras
The RAS protooncogenes encode membrane-associated guanine nucleotide binding proteins of 21 kDa. Constitutive activation by substitution of amino acid residues
at various positions is frequently found in human invasive
colorectal carcinomas and in other types of human cancer
(45). Interestingly, activated Ras cooperates with TGF-
to regulate invasion via the Raf-MAPK pathway (154, 185,
303, 399). Invasion into chick heart as well as into collagen gels was conveyed by Py-MT or by mutated (Val-12)
Ha-ras upon SLC-44 rat intestinal epithelial cells immortalized by polyoma large T but not upon Caco-2 cells,
derived from a human colonic adenocarcinoma cell line
Physiol Rev VOL
(75). Interestingly, the SLC-44 cells and its derivatives had

weak or no expression of E-cadherin, whereas all Caco-2
cells were clearly positive at the cell-cell borders. In these
experiments the effect of constitutive expression of the
oncogenes was not limited to invasion, since it also increased growth as measured after subcutaneous transplantation into nude mice. Moreover, Ha-RAS transfected
Caco-2 cells failed to perform enterocytic differentiation.
Examples of the competition between the invasion-suppressor effect of E-cadherin and the invasion-promoter
effect of activated Ras are shown in Figure 4. Clearly, in
these and in other model systems, the invasion-suppressor potency of E-cadherin did neutralize the invasionpromoter potency of the mutated Ha-Ras (432).
4. Pten
PTEN (phosphatase and tensin homolog deleted on
chromosome 10), also termed MMAC1 (mutated in multiple advanced cancers) or TEP1 (TGF- regulated and
epithelial cell enriched phosphatase 1), was the first tumor suppressor gene encoding a protein with phosphatase activity (69). The gene is located on chromosome
10q23 and is a candidate invasion suppressor because of
its late inactivation during cancer development (233, 379,
392). Its mutation frequency in human cancers is very
high and close to that of p53. Mutations were described in
high-grade but not in low-grade gliomas, independent of
p53 mutations (114, 330), in bladder cancer (65), in advanced prostate cancer, and cell lines derived therefrom
(66, 444). PTEN acts on both proteins and lipids; as a
protein phosphatase it has a dual specificity acting on
tyrosine and on serine/threonine. Its main targets as a
lipid phosphatase are phosphoinositides where PTEN dephosphorylates the three position and in this way counteracts PI 3-kinase. Clustering of mutations in the lipid
phosphatase domain, e.g., G129E, suggests that this domain is critical for the tumor-suppressor activity (284).
The involvement of the protein phosphatase domain and
the loss of expression observed in some cancers led to the
conclusion that PTEN has a dual role, regulating growth
and survival through its lipid phosphatase activity and
adhesion and invasion through its protein tyrosine phosphatase activity (392, 444). More recent experiments with
RAS or SRC transformed MDCK (MDCK-ras and
MDCKts.src) cells favor the opinion that the lipid phosphatase activity of PTEN is implicated in stabilization of
junctional complexes and restriction of invasion (218).
Indeed, successful transfection of these MDCK transformants with wild-type PTEN, but not with mutants deficient in lipid phosphatase activities, induces cellular aggregation and abolishes invasion. The implication of the
E-cadherin/catenin complex in the expression of the noninvasive phenotype was demonstrated by the proinvasive
action of antibodies that functionally neutralized E-cad-
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human cancers, including kidney (356), thyroid, pancreas,

colorectal (110, 111) and gastric cancers (231). In hereditary papillary renal cell carcinoma, missense mutations
in the MET protooncogene lead to constitutive activation
of the c-Met protein (356). Activated multifunctional
docking sites recognize SH2-containing adaptors like Grb2
and Shc, attract effector proteins such as phosphoinositide (PI) 3-kinase, Src, and phospholipase C (PLC)- and
so stimulate diverse cellular functions (327). Phosphorylation of Y1349 and Y1356 is essential for scattering; point
mutation in Y1349 abolishes the metastatic potential
whilst enhancing the transforming activity. In NIH 3T3
cells, transfected with a mutated c-MET, tyrosine phosphorylation corresponds with transforming potential, focus formation, and tumorigenicity (189). Mutant c-Met
induces motility in MDCK cells and metastatic potential in
NIH 3T3 cells; transgenic mice develop metastatic mammary cancer (188). Interestingly, the expression pattern of
the c-Met, and of other protooncogenic receptor tyrosine
kinases, with their respective ligands during embryonic
development suggests that they are involved in normal
epithelial morphogenesis as well (39).
The FGFR family consists of four genes: FGFR-1 (flg
gene), FGFR-2 (bek gene), FGFR-3, and FGFR-4. In the
rat Dunning prostate cancer model and in human prostate
cancer , progression is associated with alternative spicing
in FGFR-2 gene: early stages express the III-b isoform
dominantly binding keratinocyte growth factor (KGF) and
later stages the III-c isoform with high affinity for basic
fibroblast growth factor (bFGF) (142). FGFR1 and FGFR
2c/bek transfection into NBT-II cells leads to epithelialmesenchymal transition in response to acidic fibroblast
growth factor (aFGF) and bFGF (352). Similarly, transfection of FGFR-1 into less malignant prostate cells accelerated the progression toward a more maligant phenotype (131, 263). It is interesting to note the existence of an
FGF-2 nuclear isoform conveying metastatic properties
upon NBT-II rat bladder carcinoma cells without secretion and without the conventional FGFR-mediated signaling pathway (306).
347
348
FIG. 4. Genetic manipulation of apparently

spontaneously immortalized cell lines from dog renal (MDCK) and mouse mammary (NMuMG) origin
resulting in E-cadherin-dependent alterations of invasion in vitro. [Schematic representation of data
from Vleminckx et al. (432).]
herin. The same tranfections counteracted invasion also

in PTEN-defective cell lines derived from neuroblastoma,
melanoma, and prostate carcinoma. Like for the genes
discussed above, the product of the PTEN gene is involved not only in migration but also in proliferation and
survival (107).
F. Invasion Genes and Metastasis Genes,
Separate Classes?
The multistep invasion process of metastasis explains that invasion is a prerequisite for metastasis; it
does, however, not account for the large differences in
metastatic ability of invasive tumors. A working definition
of metastasis genes, different from invasion genes, might
be that their activation or inactivation changes the metastatic phenotype of invasive tumors. In the above-mentioned example of crosses of Rip1Tag mice with mice
expressing dominant negative E-cadherin (Rip1dnE-cad),
Physiol Rev VOL
no distinction can be made between the acquisition of

invasion and metastasis. MTS1 (metastasin 1) possibly
meets the criteria of a metastasis promoter gene because
it conveys metastatic capability upon invasive nonmetastatic tumors (4). Mice of the GRS/A strain carry a mouse
mammary tumor virus (MMTV) provirus and have a high
incidence of mammary tumors, due to the proviral activation of the oncogenes WNT and INT-2. Histologically,
these tumors represent moderately differentiated invasive
adenocarcinomas. The GRS/A mice were crossed with
transgenic mice expressing the MTS1 gene in the lactating
mammary gland under the control of an MMTV promoter.
These MTS1 transgenics do not develop mammary tumors. Successful crosses between GRS/A and MTS1 mice
have mammary cancers that are not only locally invasive
but also form metastases in the lungs. Here, MTS1 acts as
a metastasis-promoter gene, but the phenotypic alteration
responsible for the formation of metastases from invasive
primary cancers is not clear.
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CANCER INVASION
G. Noncancer Invasion-Suppressor
and Invasion-Promoter Genes
Physiol Rev VOL
plcB), the two others (inlA and inlB) form a distinct

operon. All these genes are coordinately regulated by
PrfA, the trancriptional activator encoded by the prfA
gene (268). Such a gene, switching on and off coordinated
invasion programs, has not been found in cancer cells, so
far. The invasive, virulent, and pathogenic E. histolytica
differs genetically from the noninvasive, avirulent, and
nonpathogenic E. dispar as evidenced by restriction fragment length polymorphism and sequencing of single copy
genes (320). Here, like in bacteria, virulence genes are
crucial for invasion; downregulation of their expression
by antisense RNA transfections causes a reduction of
invasion-associated molecules such as amoebapore (54),
the 35-kDa light subunit of the Gal/GalNac specific lectin
(8) and the cysteine proteinase 5 (9). The life cycle of the
parasite Schistosoma mansoni provides an example of
spatiotemporal regulation of an invasion-promoter gene
at the cercaria stage. Before the cercaria leaves its snail
host to swim freely in the water, the gene encoding a
serine protease is switched on. This powerful lytic enzyme is activated only upon contact with the human skin
and in this way acts exclusively at the site of invasion.
Once the cercaria has invaded into the dermis of its new
host, the protease gene is switched off (132).
Taken together, the above-mentioned examples of
invasion-suppressor and invasion-promoter genes clearly
demonstrate that multiple genes are implicated in invasion and that they vary between different types of cells.
Their activation or inactivation triggers programs of cellular activities that are rarely restricted to invasion and
usually changes also the other cellular activities depicted
for cancer cells in Figure 1.
IV. CANCER CELLS, HOST CELLS, AND TUMOR
CELLS: ALL INVADERS
A. Cancer Cells and Host Cells
Cellular behavior and gene activation or inactivation
are greatly influenced by the environment in normal as
well as in pathological situations including cancer (see
Fig. 1). The Lancets first volume (313) launched the seed
and soil hypothesis asking the question: What is it that
decides what organ shall suffer in a case of disseminated
cancer? His answer is still valid: The microenvironment
of each organ (the soil) influences the survival and growth
of tumor cells (the seed). Pathologists have since a long
time recognized that tumors contain not only neoplastic
cells, further called cancer cells, but also host cells. The
host participation at the establishment of the tumor is
described as desmoplasia, consisting of fibroblastic cells
and extracellular matrix, as inflammation and immune
response represented by lymphocytes, macrophages, and
dendritic cells, and as angiogenesis evidenced by newly
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During normal embryonic development, spatiotemporal activation and inactivation of invasion-promoter

genes and invasion-suppressor genes participate at the
regulation of gastrulation and morphogenesis. The idea to
consider some of the proteins encoded by these genes as
promoters or suppressors of cancer invasion came from
embryology (390). For example, E-cadherin is first expressed at the morula stage, hence its former name uvomoruline, where it serves compaction, the earliest form of
epithelial organization (178, 224). At the onset of gastrulation, when cells start to migrate from the ectoderm
undergoing an epithelial to mesenchymal conversion, Ecadherin is downregulated and N-cadherin is expressed.
This switch of cadherin expression from DE- to DN-type
(D for Drosophila) occurs downstream of the invasion
promoter genes Twist and Snail (302). Twist encodes a
nuclear protein containing a helix-loop-helix motif, which
probably acts as a transcription factor. At gastrulation in
Drosophila melanogaster, Twist-positive cells roll into
the presumptive mesoderm, as beautifully illustrated in
Reference 226; Twist / mutants, like Snail / mutants, fail to complete gastrulation (68). Morphogenetic
activities that act through activation of the E-cadherin
gene are found also in hepatocytes, through the CDH1binding transcription factor hepatocyte nuclear factor
(HNF)-4 (375) and in thyrocytes, through thyroid stimulating hormone (52). Reversion of an invasion-associated
phenotype, namely, mesenchymal to epithelial transition,
is observed during metanephrogenesis. This transition
was mimicked in the human fetal kidney cell line HEK293
where expression of PAX-2, a member of the paired-box
homeotic gene family, was associated with a gain of Ecadherin and -catenin expression (408).
In microorganisms, virulence genes are regulators of
invasion. Historically, the first transformation from nonvirulent into virulent Streptococcus pneumoniae formed
the basis for the identification of DNA as the genetic
material by Avery et al. (12). Transfection was applied to
the analysis of specific invasion genes first in bacteria
(181). Transfer of a single genetic locus from the invasive
bacterium Yersinia pseudotuberculosis made the noninvasive Escherichia coli invasive into cultured vertebrate
cells. When the noninvasive L. innocua is transfected
with a plasmid harboring the internalin A (inlA) gene, the
bacterium becomes invasive into Caco-2 cells (141). The
invasion assay took advantage of the fact that invaded,
hence intracellular, bacteria are protected against antibiotics that fail to penetrate into the cells (see Fig. 3). In
Listeria, virulence genes regulate not only entry into the
vertebrate cell, but also intracellular multiplication and
spreading. Six of these virulence genes are clustered on
the bacterial chromosome (prfA, plcA, hly, mpl, actA, and
349
350
of this review is on the continuous molecular cross-talk

between the cancer cells and the host (Fig. 5). Cytokines,
such as TGF- and platelet-derived growth factor
(PDGF), are released from the cancer cells, probably at a
proinvasive state of tumor development; they stimulate
the transition of fibroblasts into myofibroblasts. The latter
cells are found, indeed, more frequently in preinvasive
lesions of the colon such as villous adenomas and FAP,
that have a higher risk of transition into invasive carcinoma, than in lesions such as tubular adenomas, that have
a lower risk of progression (260). Myofibroblasts do participate at numerous noncancerous pathological and
physiological processes. During wound healing they assist
at migration, proliferation, and contraction. When the
wound is closed, myofibroblasts undergo apoptosis, quite
in contrast to tumors where they persist as in a wound
that does not close (115). This idea illustrates that cancer
cells operate by noncancer specific activities, but they fail
to regulate these activities properly. Myofibroblasts produce numerous molecules, growth and motility factors,
angiogenic factors, extracellular matrix components, and
proteinases, that all promote the invasion and also the
growth of cancer cells. Other molecules of putative interest for invasion expressed by myofibroblasts include
-smooth muscle actin, vimentin, c-MET (404), proteolytic FAP displaying also dipeptidyl peptidase activity
(316), cyclooxygenases (COX)-1 and -2 and N-cadherin,
associated with -catenin, -catenin, p120CTN, and Tcatenin (187, 425). An early demonstration of the invasion-stimulating activity of myofibroblasts resulted from
the differential behavior in vitro compared with in vivo of
PROb cancer cells that were isolated from a chemically
induced rat colon tumor (108). PROb cells invaded neither into collagen nor into Matrigel nor into embryonic
chick heart in culture. Upon subcutaneous injection into
syngeneic rats, PROb cells did, however, produce invasive
cancers, and numerous myofibroblasts were present at
the front of invasion in line with observations on human
cancers. PROb cells were stimulated to invade also in
vitro, provided myofibroblasts were added to the culture
system. These myofibroblasts themselves were also invasive. One interesting example of noncancerous myofibroblast invasion is described in experimental tubulointerstitial fibrosis (288, 386). There is good histological and
ultrasctructural evidence to accept that tubular epithelial
cells transdifferentiate into myofibroblasts invading
through a disrupted basement membrane into the underlying stroma. Like in cancer, TGF- produced by the
tubular epithelial cells stimulates fibrosis (322).
B. Myofibroblasts: Stimulators of Invasion

C. Angiogenesis Before Invasion
The role of myofibroblasts, first described as smooth
muscle-like fibroblasts by Gabbiani et al. (140), in cancer
invasion has been recently reviewed (106). The emphasis
Physiol Rev VOL
Blood vessels and lymph vessels provide tumors with

nutrients and cytokines, necessary for growth and inva-
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formed blood and lymph vessels. These host elements,

although more abundant in some types of cancer than in
others, are omnipresent. For example, less than half of
most pancreatic cancers are occupied by cancer cells, the
majority being host cells. In line with this histological
observation is the detection of a cluster of invasion-specific expression of genes encoding molecules that participate at the reaction of the host (345).
There are clinical and experimental data to believe
that host cells play a major role in invasion and metastasis. Metastasis may depend on the specific site of the
primary cancer. The frequency of distant metastasis from
squamous cell carcinomas of the head and neck region
depends on the subsite of the primary cancer, varying
from 3.1% for tumors situated in the larynx to 28.1% for
tumors in the nasopharynx as summarized in Reference
249. More recently, the latter figure has increased to 40%
as new treatment techniques such as intensity modulated
radiotherapy (IMRT) have improved local tumor control
and patient survival (388). Orthotopic, compared with
paratopic (usually indicating subcutaneous), implantation
into immunosuppressed mice provides an experimental
demonstration of site specificty of invasion and metastasis. When human colon cancer cells are implanted in the
wall of the cecum (325) or when oral squamous cell
carcinoma cells are implanted into the tongue of nude
mice (202), they invade and metastasize in contrast to
their subcutaneous counterparts. Organ specificity indicates that some tumors metastasize more frequently to
specific organs than could be expected from their transport in the circulation and their passage through capillary
networks. Examples of preferentially affected organs are
the brain for lung cancer and melanoma and bone for
prostate and breast cancers (436). It is still a matter of
debate whether organ specificity of metastasis is due to
specific homing and extravasation or to specific survival
and growth of the cancer cells at the site of extravasation.
The type of host cells, e.g., endothelial cells, that participate at tumor development all are invasive themselves
and some, e.g., leukocytes, are even metastatic. It is,
therefore, justified to ask the question who is invading
who (238). The recruitment of host cells is most likely the
result of the production by the tumor microecosystem of
stimulatory and inhibitory factors. Moreover, these host
cells may proliferate in the tumor ecosystem, again governed by balances between inhibitory and stimulatory
factors. Cancer cells may also cause transdifferentiation
of host cells, e.g., fibroblasts into myofibroblasts.
351
CANCER INVASION
FIG. 5. Micro-ecosystem of a primary cancer.

Cellular activities associated with invasion implicate reduced cell-cell adhesion, altered cell-matrix
adhesion, migration, ectopic survival, and lysis of
extracellular matrix. Most of these activities are
modulated by the cross-talk between cancer cells
and host cells, which are activated by cytokines
released from the cancer cells. [Adapted from Mareel et al. (251) and De Wever and Mareel (106).]
Physiol Rev VOL
enovirus vector carrying the human PAI-1 cDNA restored

angiogenesis and invasion. The molecular explanation is
that plasmin proteolysis must be tightly controlled to
allow vessel stabilization and differentiation.
D. Tumor Infiltrated Leukocytes:
Helpers of Invasion
Tumor tissues are frequently infiltrated by host leukocytes, sent in by the immune system of the host in an
attempt to reject the tumor. Indeed, some of these host
cells are able to kill cancer cells or to secrete antiangiogenic factors. A recent example is provided by the high
susceptibility to skin carcinogenesis of mice lacking T
cells (149). It is, however, evident that such infiltrated
cells can also have tumor-promoting effects. This may be
illustrated by the earlier finding that nonmetastatic lymphoma cells become metastatic upon fusion with activated leukocytes (96). The countercurrent principle originally developed in chemistry to separate oil lovers from
water lovers and, later, in Drosophila genetics of behavior
to separate light lovers from dark lovers, was applied to
the helper function of leukocytes in invasion (308). Cancer cells produce chemotactic cytokines (called chemokines), a family of small proteins that attract leukocytes
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sion; they provide the routes for systemic spread of cancer cells; and they mediate the communication between
the primary tumor and its metastasis (309). These vessels
represent the response of existing blood and lymph vessels to balances between positive and negative angiogenic
factors produced by the cancer cells. The type of vessels,
hematogenic or lymphatic, that are invading the tumor
might be determined by the type of vascular endothelial
growth factor (VEGF) produced (368). Because invasion
into vessels initiates metastasis, the type of VEGF might
also determine the route of metastasis, lymphogenic or
hematogenic. In exceptional cases, the cancer cells themselves may transdifferentiate into endothelioid cells and
form the tumor vascular system, a phenomenon that is
called vasculogenic mimicry (244). Several excellent reviews on tumor angiogenesis were produced (70, 134,
207). We would, therefore, limit the discussion to the
observation that neoangiogenesis may be needed for primary invasion as well as it is for growth as evidenced by
an in vivo mouse model (14, 15). Transplantation of collagen gels coated with malignant murine keratinocytes on
the dorsal muscle fascia of wild-type mice resulted in
invasive squamous cell carcinomas. When plasminogen
activator inhibitor (PAI)-1 / knock-out mice were
used, the cancer cells failed to invade, and there was no
angiogenesis. Intravenous injection of a recombinant ad-
352
from the circulation along a chemical gradient toward the

tumor. These chemokines also stimulate the production
of MMPs by the attracted leukocytes, that dissolve the
extracellular matrix (ECM) on their way to the tumor. By
doing so, a tunnel is created for the invading cancer cells
(Fig. 6). Moreover, the chemokines act as growth factors
for the cancer cells and are angiogenic, so providing
vessels that mediate invasion and serve as routes for
metastasis.
E. Osteoclasts: Targets for Therapy
FIG. 6. Schematic of the countercurrent model of leukocyte-assisted

cancer invasion, as proposed by Opdenakker and Van Damme (308).
Physiol Rev VOL
F. Molecular Cross-Talk in
Noncancerous Situations
Epithelial-mesenchymal interactions are crucial in
morphogenesis (158, 367). In adults, invasive and metastatic normal leukocytic stem cells are retained in the
bone marrow through adhesion to stromal cells. Microbial
invasion is to a large extent governed by host factors.
Species specificity is a striking example of host-determined invasion. L. monocytogenes invades human,
chicken, rabbit, and guinea pig intestine but neither
mouse nor rat, a phenomenon that is explained through
single amino acid differences in the first extracellular
domain of the enteric E-cadherin, serving as the receptor
for the bacterial virulence factor inlA. In amoebiasis,
caused by E. histolytica, human species specificity is
explained by the transformation from noninvasive cysts
to invasive trophozoites depending on a number of human
host cell factors such as acid in the stomach, pancreatic
enzymes, low oxygen content, inorganic salts, and microflora (148). Organ specificity of metastasis is illustrated in
leishmaniasis. According to the type of leishmania, lesions will develop at the site of injection in the skin (L.
ropica) or in the mucocutaneous tissues of the respiratory and the genital tract (L. brasiliensis) or in the viscera, mainly liver and spleen (L. donovani). Although the
exact mechanisms of this organ specificity are unknown,
immune mediators may be involved, since the cutaneous
forms of leishmaniasis also affect the viscera in HIVpositive individuals. Examples of parasites that are transported by host cells, a kind of passive invasion, are
Trypanosoma and Leishmania using macrophages and
Plasmodium merozoites using erythrocytes (200).
The genomic alterations in epithelial cells, which
lead to cancer, disturb the molecular conversation between the epithelial cells and the underlying stroma. As a
consequence, the cancer cell population, developing at
the primary tumor site, attracts host cells and so creates
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In bone metastasis, a frequent complication in malignant tumors, cancer cells subvert the host dynamic homeostatic mechanisms that preserve the structure and
function of the skeleton. The result is excessive breakdown of bone, pain, and eventual fractures. Cancer cells
release osteoclast activating factors, such as interleukin-1, tumor necrosis factor, TGF-, epidermal growth
factor (EGF), PDGF, and prostaglandins, and activated
osteoclasts cause breakdown of bone matrix (Fig. 7). This
breakdown is probably not limited to osteoclasts as it has
been attributed also to cancer cells and even to osteoblasts and osteoblast-like cells (221). Bone matrix break-
down releases chemotactic factors attracting cancer cells

and growth factors stimulating their proliferation. Osteoclasts are successful targets for treatment of bone metastasis by bisphosphonates acting through inhibition of osteolytic activity, fortifying bone matrix and interfering
with the formation of osteoclasts from monocytes (172,
282). Bisphosphonate acts not exclusively on osteoclasts
as it induces also apoptosis in human breast cancer cells
in experimental animal models. The naturally occurring
decoy receptor osteoprotegerin, a member of the tumor
necrosis receptor family, also inhibited metastatic osteolysis and decreased tumor burden in experimental models
(278). Osteoprotegerin antagonizes the binding between
the osteoclast RANK receptor and its ligand, which is
necessary for osteoclast differentiation.
353
CANCER INVASION
a dynamic tumor microecosystem in which there exists a

continuous cross-talk between the cancer cells and the
host cells. Such microecosystems are created at each step
of invasion by cancer cells and also by normal cells and by
microbial organisms. The type of elements participating
at these microecosystems is somewhat different for each
of the invasive steps. A characteristic of an ecosystem is
that alteration of a single element may dramatically
change the entire system. The transition from the noninvasive, i.e., maintenance of normal tissue architecture or
absence of invasion, to an invasive phenotype within the
microecosystem constitutes such a dramatic change that
may equally depend on alterations in elements of the host
or in the potentially invader population (see Fig. 5).
Physiol Rev VOL
V. CELLULAR ACTIVITIES ASSOCIATED WITH

THE INVASIVE PHENOTYPE
Cellular activities positively or negatively associated
with the invasive phenotype comprise cell-cell adhesion,
cell-matrix adhesion and ectopic survival, migration, and
proteolysis (see Fig. 5). In cells that have progressed
toward malignancy through activation of promoter genes
and inactivation of suppressor genes (see Fig. 1), these
cellular activities are regulated by autocrine and paracrine ligands, resulting in modulation of the invasive phenotype. The challenge is to trace the pathways from the
ligand to the receptor to the signal transduction and finally to the cellular response that is crucial for the alter-
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FIG. 7. Schematic of the micro-ecosystem of

bone metastasis. Bisphosphonates inhibit osteoclastic bone destruction and so counteract the
further development of bone metastasis. E-cadherin is implicated in the fusion of osteoclast precursor monocytes. [Modified from Mareel et al.
(249).]
354
ation of the invasive phenotype. Methods used implicate

the genetic manipulation of cells to change their sensitivity toward putative invasion modulators and the use of
pharmacological inhibitors targeting specific elements of
the signaling pathways. Such signaling pathways can be
presented in a linear fashion, connecting the initiating
event, e.g., activation of a receptor tyrosine kinase by
ligand binding, to the activation of gene expression in the
nucleus. However, signal transduction pathways have
many potential branch points that provide opportunities
for signaling cross-talks, and most invasion pathways are
complex with multiple branch points rather than simply
linear (113). In the latter scenario, it is expected that the
most highly connected proteins are the most important
ones for the cells most vital functions (190). The number
of molecules and networks implicated in invasion-associated cellular activities has increased to the point that a
comprehensive review falls beyond the scope of the
present review. As announced earlier, the following discussion deals with selected examples.
Homotypic (between cells of the same type) epithelial cell-cell adhesion counteracts the escape of cells into
neighboring tissues and, even, invasion by well-differentiated epithelial strands implicates some degree of weakening of cell-cell adhesion, as demonstrated in a direct
way for the first time by Coman (80). Heterotypic cell-cell
adhesion, e.g., between circulating cancer cells and the
vascular endothelium, promotes invasion through the vascular wall and the initiation of metastases. On rare occasions, homotypic cell-cell adhesion may promote invasion, mediating apical implantation of cancer cells into
the bladder mucosa (331) or lymphovascular permeation
in inflammatory breast cancer (407).
1. Homotypic cell-cell adhesion: the
E-cadherin/catenin/actin pathway
The prototype homotypic epithelial cell-cell adhesion
molecule operating through homophyllic interaction is
E-cadherin. Adherens junctions are the structure in which
E-cadherin operates. Other intercellular junctions, mentioned as putative players in invasion, are tight junctions,
desmosomes, and gap junctions. We have provided evidence (see sect. III) in favor of an invasion-suppressor
function of E-cadherin. The question is whether or not
homotypic cell-cell adhesion is responsible for suppression of invasion. E-cadherin is certainly suited for such
function as dimers on one cell form stable molecular
bonds with E-cadherin dimers on another cell. Such extracellular interaction is sufficient for a relatively weak
adhesion, whereas stronger adhesion necessitates also
intracytoplasmic interactions of E-cadherin (60) and an
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A. Cell-Cell Adhesion
intact transmembrane domain (177). In many experiments a positive correlation was found between lack of
invasion and cell-cell adhesion in vitro, the E-cadherin
specificity of both phenotypes being demonstrated with
the aid of functionally inactivating antibodies. (30, 46, 81,
253, 296, 390, 423). The expression of large proteoglycans
such as episialin, also called MUC-1, may sterically hinder
the homophilic interactions of E-cadherin and so contribute to invasion of cancer cells (380, 433). In vivo,
Rip1dnE-cad mice, overexpressing a dominant negative
form of E-cadherin in pancreatic -cells (see sect. III),
showed a transient perturbation of -cell aggregation during islet development (91). Other homotypic cell-cell adhesion complexes have also been implicated in invasion.
Desmosomes are considered as regulators of epithelial
structure and as invasion suppressors by some authors,
and the experimental arguments resemble the ones put
forward for adherens junctions (342, 413). These authors
presume that desmosomal cadherins and E-cadherin are
comparably involved in the maintenance of the epithelial
structure. L929 fibroblasts transfected with desmosomal
components, namely, desmocollin, desmoglein, and plakoglobin, become adhesive and noninvasive, and these reverted phenotypes are lost upon addition of short peptides
corresponding to cell-cell adhesion recognition (CAR) sites
of desmosomal cadherins. Furthermore, downregulation of
desmosomal adhesion molecules correlates with invasion
and metastasis in some human cancers without consideration of the E-cadherin status (95, 287). In invasive and
metastatic cancers of the oral cavity, downregulation of
desmosomal cadherins was associated with loss of Ecadherin (364). Gap junctions are membrane-spanning
channels composed of protein subunits called connexins;
they facilitate intercellular communication through small
(Mr 1,000) molecules. Such junctions may act as invasion
promoters, since transfection with connexins and homotypic coupling lead HeLa cells to invade into chick heart
fragments in organ culture (156). In human breast cancer
cell lines, relative amounts of different connexins were
held responsible for metastasis (350).
Although most attention has been paid to the cell-cell
adhesion function of E-cadherin, it can certainly not be
excluded that other invasion-associated cellular activities
are implicated. Loss of E-cadherin, eventually associated
with upregulation of N-cadherin, may stimulate migration
and so promote invasion (55, 163). In cancer of the prostate (406, 409) and of the head and neck mucosa (182),
migration of epithelial cells coincides with the loss of
E-cadherin and is sometimes accompanied by a gain of
N-cadherin expression. The E-cadherin/catenin complex
is implicated also in directed migration during epithelial
wound healing, presumably through contact inhibition of
membrane ruffling (6, 81) and in intercellular motility
during epithelial morphogenesis (158). This is in line with
the observation that a monoclonal antibody against E-
CANCER INVASION
E-cadherin/catenin complex in various manners: alterations of the binding of the complex to actin; disturbance
of the signaling function through conformational changes
that hamper the cross-talk with other proteins; and recruitment of new partner proteins that possess phosphotyrosine-specific binding domains. Abrogation of EGFRinduced tyrosine phosphorylation of -catenin inhibits
invasion of melanoma cells (44). Furthermore, the -catenin binding site of E-cadherin shows Pro-Glu-Ser-Thr
(PEST) sequences, candidates for degradation by the
ubiquitine/proteasome pathway, so that binding of -catenin prevents the cytoplasmic tail of E-cadherin from degradation (176). -Catenin links the E-cadherin/catenin
complex to the actin cytoskeleton (337). Successful transfection of -catenin-negative adhesion-deficient variants
of the HCT-8, coined HCT-8/R, colon cancer cell line with
T- or E-catenins restored cell-cell adhesion and compaction (187). p120 catenin is encoded by CTNND1 on
11q11 (205). In cancer cells, p120CTN can be found at the
membrane and in the nucleus, where it binds to the zinc
finger transcription factor Kaiso (94, 424). Unlike -catenin, p120CTN is not degraded through interaction with the
APC/GSK-3 complex. Larger aggregates were formed by
FIG. 8. The E-cadherin/catenin and the wnt/-catenin signaling pathways. For detailed description, see sections III
and V. Definitions are as follows: APC, adenomatous polyposis coli protein; Cdc42, cell division cycle 42, a small
G protein; CTN, catenin; DSH, dishevelled; EB1, microtubule end binding protein1; E-CAD, E-cadherin; Frz, frizzled; GF,
growth factor; GSK-3, glycogen synthese kinase-3b; ILK, integrin-linked (serine/threonine) kinase; IQGAP1, GTPaseactivating protein; Kaiso, transcription factor of the Pox virus and zinc finger superfamily; LEF, leukocyte enhancer
factor; MMP-7 (matrilysin), matrix metalloproteinase-7; PI3-K, phosphoinositide 3-kinase; PKB, protein kinase B; PTP,
protein tyrosine phosphatase ; Rac, Ras-related C3 botulinum toxin substrate; Ras, small GTPase of the Ras homolog
family; Rho, Ras homolog; RTK, receptor tyrosine kinase; Shp-1, SH2 domain protein tyrosine phosphatase; Src, tyrosine
protein kinase encoded by the cellular protooncogene homologuous to the viral Rous sarcoma oncogene v-SRC; Smad3,
Mad (mothers of decapentaplegic)-related protein 3, recognizing a palindromic DNA sequence; TFF, trefoil factors; Wnt,
vertebrate homolog of Wingless. [Adapted from Van Aken et al. (419), with data from McCartney and Peifer (266), Mu ller
et al. (281), Lickert et al. (235), Kuroda et al. (219), and Wu et al. (451).]
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cadherin neutralizes the invasion-stimulating effect of bile

acids on colon cancer cells in vitro (97). Finally, there
exists good evidence to accept that E-cadherin downregulation stimulates growth and ectopic survival (197, 378).
The molecular organization and the links of the Ecadherin/catenin complex with multiple other receptor
and nonreceptor signal-tranducing systems make it very
likely that alterations of an element of the complex affects
multiple cellular activities (Fig. 8). Next to the genetic and
transcriptional regulation discussed in section III, the Ecadherin/catenin complex can be structurally and functionally downregulated at the posttranscriptional levels in
many ways, including phosphorylation (323), glycosylation (457), proteolysis (295), endocytosis (47), and sterical hindrance (171, 380, 433). Consequently, there exist
many natural and pharmacological agents that stimulate
or inhibit invasion of cells by direct or indirect action on
the E-cadherin/catenin complex (See Table 3 in Ref. 419).
Armadillo repeats, as present in -catenin, plakoglobin,
and p120CTN, are good substrates for tyrosine kinases
(93). Indeed, tyrosine phosphorylation of -catenin by
nonreceptor kinases, like Src (31), and receptor tyrosine
kinases like EGFR (365) and c-Met (363), perturbs the
355
356
cells that were transfected with wild-type E-cadherin

compared with E-cadherin mutants, to which p120CTN
failed to bind (403). Current views hold that p120CTN
induces E-cadherin clustering and cell-cell adhesion by
binding to the juxtamembrane part of E-cadherin and that
intracellular signaling can induce an inactive form of
p120CTN (312, 403). Tyrosine phosphorylation of p120CTN
increases its affinity for the juxtamembrane domain of
type I cadherins and lowers its affinity for RhoA. RhoA,
uncoupled from 120CTN, could subsequently be activated
by GEFs guanine nucleotide-exchange factors (GEFs)
with further downstream RhoA signaling and promotion
of cadherin clustering (5). Dephosphorylation of p120CTN
is mediated by the protein tyrosine phosphatases SHP-1
(204) and protein tyrosine phosphatase (PTP) (459).
The interaction between the E-cadherin/catenin complex
and the cytoskeleton is probably not limited to actin but
also implicates microtubules that are stabilized at cell
contacts by signaling from cadherins (76).
2. Heterotypic cell-cell adhesion
VA.
FIG. 9. Heterotypic cell-cell adhesion at the site of extravasation in the brain. For detailed description, see section
[Adapted from Mareel et al. (251).]
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Heterotypic homophylic cell-cell adhesion may have

an invasion-suppressor function. Melanocytes and antigen-presenting dendritic cells are retained in the epidermis through homophylic E-cadherin-mediated binding to
keratinocytes (394, 395) and downregulation of E-cadherin is characteristic for invasive melanoma (175). An
invasion-promoter function of heterotypic homophylic interactions was inferred from N-cadherin-mediated coaggregation of breast cancer cells and stromal cells (166).
Similar conclusions were drawn from the invasion of

N-cadherin-positive human prostate cancer cells into the
diaphragm of SCID mice (409).
Heterotypic heterophylic cell-cell adhesion may also
exert invasion-suppressor as well as invasion-promoter
functions. Retention of lymphocytes in their target epithelium is mediated by heterophylic interaction between Ecadherin and the E7-integrin, respectively, on epithelial
cells and on T lymphocytes (74, 85). Heterotypic adhesion
between circulating cancer cells and endothelial cells
leads to extravasation and initiation of metastasis (Fig. 9).
The scenario, similarly applicable to leukocytes and cancer cells, comprises rolling of the invaders over the endothelium through high-avidity low-affinity interaction between selectins and their carbohydrate ligands. One
additional earlier step is suggested by the observations of
Glinsky et al. (152), indicating that circulating T (Thomsen-Friedenreich) antigen bearing glycoproteins produced and released by the primary tumor might stimulate
endothelial cells to express galectin-3 at their surface.
Endothelial galectin-3 would mediate the initial docking
of the circulating cancer cells through binding to the T
antigen on the surface of the cancer cells. Chemokines
form a chemotactic gradient on the endothelium, and
their interaction to G protein-coupled serpentine receptors on the invaders leads to activation of integrins. The
latter interact with IgCAMs on the endothelium and so
realize a more stable arrest by low-avidity high-affinity binding of the invader cells, initiating migration between the
endothelial cells. During this ultimate step, the homophylic
CANCER INVASION
cell-cell adhesion molecule CD3 comes into play (333, 373,

376, 438). It is quite clear that in all these examples the
interaction between cancer cells or leukocytes and host
cells is not limited to physical adhesion but also initiates
complex signaling pathways that may affect growth, differentiation, and survival of the interacting cells. In such signaling, cytoskeletal reorganization plays a major role (307).
Intracellular invasion of most microorganisms is initiated by heterotypic heterophylic adhesion. The example is
binding of the virulence factor of L. monocytogenes, internalin A to E-cadherin on enterocytes (227). Internalin A-deleted mutants fail to invade into enterocytes, and enterocytes that fail to express E-cadherin with a proline at
position 16 are not permissive for invasion by Listeria (Fig.
10). Mouse E-cadherin has a glutamic acid at position 16,
and mouse epithelial cells do not permit invasion of Listeria. In transgenic mice, expressing human E-cadherin, with
a proline-16, under the control of an iFABP promoter (intestinal isoform of the fatty acid binding protein), internalinmediated invasion into the enterocytes and crossing of the
intestinal barrier by Listeria did occur (229). As described
357
above for cancer cell/host cell adhesion, binding of the

bacterial virulence factors to the vertebrate receptor initiates a signaling cascade that engages the host cell machinery in bacterial entry (88). Other examples of invasion-associated molecular cross-talk are found with the HIV virus,
where the gp120 viral surface glycoprotein binds to the
leukocyte CD4 receptor and exposes the gp120 V3 variable
domain for binding with a CC chemokine receptor (240).
Remarkably, enteropathogenic E. coli (EPEC) translocate
their own intimin receptor into the host cell which then
binds to intimin on the bacterial surface (417).
B. Cell-Matrix Interactions
The ECM is a key player in the activities that are
crucial for normal cell behavior and tissue maintenance
(241). In invasion, the ECM and its cellular integrin and
nonintegrin receptors are implicated as a barrier, a signal,
and a substrate for invasion; as a source of growth and
motility factors; and as a regulator of survival (427). For
FIG. 10. Heterotypic (between bacteria and enterocytes) and heterophilic (between E-cadherin and internalin A;
between the c-Met receptor and internalin B) adhesion necessary for the invasion of L. monocytogenes into vertebrate
cells. For detailed description, see section VA. [Schematic was adapted from Lauwaet et al. (225), with data from
Mengaud et al. (269), Lecuit et al. (227, 228), Braun et al. (59), Shen et al. (362), and Cossart (87).]
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358
Physiol Rev VOL
strate contacts for growth and survival. Focal adhesion

kinase (FAK) is a 125-kDa nonreceptor protein tyrosine
kinase that is essential for signaling from the extracellular
matrix to the actin cytoskeleton. Cell-substrate attachment, mediated by the direct interaction of integrin extracellular domains with the extracellular matrix, leads to
clustering of integrins, recruitment to the focal adhesion
complexes, and tyrosine phosphorylation of FAK (317).
Focal complexes at the leading edge thus provide the cell
with directionality for cell movement. The formation
and remodeling of such focal contacts is a dynamic process regulated by protein tyrosine kinases and small GTPases of the Rho family (203). Exogenous PRGF1 promotes
integrin clustering and invasion of breast carcinoma cells
(412). PRGF1 activates FAK in breast carcinoma cells and
in FAK-transfected MDCK cells and stimulates cellular
migration through filters coated with collagen type I, laminin, or fibronectin (37, 222). Src phosphorylation regulates cross-talk between the E-cadherin complex and the
integrin complex and determines invasion of hepatocellular carcinoma cells (143). 64-Integrins are ligands of
laminin and key components of hemidesmosomes, linking
epithelial cells to the basement membrane. They serve not
only mechanical linkage but also molecular signaling
(270, 292). Invasion is associated with disruption of
hemidesmosomes. This may be the consequence of phosphorylation of the 4 cytoplasmic domain by the EGFR
activating the small GTPase Fyn (255). In stable, immobilized cells, 64 is linked to intermediate filaments,
whereas in migrating cells, it relocates to actin filaments.
When cells express the invasive growth program, 64
associates with c-Met and signals independently from its
interaction with the ECM (411).
Cell/substrate adhesion and communication is also
implicated in invasion by microorganisms, as reviewed
for bacteria by Patti and Ho o k (318). In the parasite E.
histolytica, integrin-like receptors bind fibronectin and
subsequently signal through protein kinase C, Rac/Rho to
the actin cytoskeleton or through the mitogen-activated
protein kinase pathway to transcription factors, elements
also encountered in cancer invasion pathways (271). Fibronectin is subsequently degraded, generating fragments
with chemotactic and chemokinetic properties. Borrelia
burgdorferi, the causative agent of Lyme disease, binds to
dermal collagen via the collagen-associated proteoglycan
decorin for which it expresses the decorin-binding proteins DbpA and DpbB (159). The crucial role for this
interaction in bacterial invasion is demonstrated by the
finding that decorin-deficient mice are resistant to Lyme
disease (62).
C. Migration
Migration is an essential activity of invading cells as
they translocate from one tissue into another, from one
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cancer cell migration, a dynamic formation and dissolution of cell-substrate contacts is needed, and ECM receptors are expected to have a dual function as they serve
adhesion to the matrix necessary for migration as well as
arrest of cells inside the matrix. To coordinate all these
functions, multiple extracellular and intracellular networks as well as fine tuning signaling are necessary.
Structurally, cell-substrate adhesion is manifested by
smaller focal complexes at the leading edge of migratory
cells, larger focal adhesions at the end of actin stress
fibers all over the surface of static cells, and hemidesmosomes between epithelial cells and the basement membrane.
Cellular receptors for ECM molecules belong mainly
to the integrin family. They recognize unique short amino
acid sequences, such as RGD, in the ECM molecules.
Integrins are integral membrane cell surface glycoproteins composed of two subunits and linked by disulfide bonds; the combination of different subunits determines ligand specificity (146). Several ECM molecules are
recognized by more than one integrin. Ligand binding can
be modulated by associated membrane molecules, by
lipid composition of the membrane, and by external factors. Integrins can be in the off or on state depending on
the conformation of the extracelular part of the molecule,
and this state might be regulated by small GTPase of the
Ras family (203). The latter may be changed by divalent
cations and by changes of the intracellular part of the
molecule. Trends of expression in tumors are exemplified
by failure to express v3, 21, and 41 in early stage
melanoma and abundant expression of the same integrins
in later stage more aggressive melanomas (361). Epithelial cancers tend to express fewer integrins, e.g., 64, and
they do so in a disorganized pattern (256). ECM/integrin
interactions are implicated not only in invasion but also in
differentiation, proliferation, and regulation of apoptosis
(49, 137, 393, 428). Invasive cells leave their natural ECM
context above the basement membrane and arrive in a
completely different ECM in the stroma. When such cells
fail to switch on survival pathways, they go into a form of
apoptosis called anoikis. Failure of immortalized cell lines
to produce benign, noninvasive tumors upon subcutaneous injection in appropriate hosts, in which their invasive
counterparts did produce invasive tumors, indicates the
association between invasion and ectopic survival. When
implanted orthotopically, i.e., above the stroma, noninvasive keratinocytes produce a viable surrogate epidermis
(369). Integrins transduce signals that regulate anchorage
dependence of growth and growth factor receptors, and
integrins show very similar signaling pathways (357). Anchorage-independent, growth factor (serum)-dependent
cell proliferation is a valuable counterpart of ectopic survival. In such model, activation of tumor promoter genes
encoding elements of the integrin signaling pathways may
overcome the necessity of integrin-mediated cell/sub-
CANCER INVASION
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invasion of pharmacological inhibitors and of transfection

with genes encoding dominant negative proteins was
evaluated. An overview of the pathways possibly implicated in these recent observations is presented in Figure 11.
1. SF/HGF/plasminogen related growth factor-1,
and the c-Met receptor
Plasminogen-related growth factor-1 (PRGF-1), also
called SF/HGF, is a paradigm motility factor that stimulates invasion in many cell types (191, 265, 441). It was
recognized by Stoker et al. (383) as a motility factor
produced by fibroblasts and causing an epithelioid to
fibroblastic morphotype transition in cultured epithelial
cells and identified by Weidner et al. (440). PRGF-1 is
produced by cancer-associated myofibroblasts (404) and
evokes multiple cellular responses through binding to its
tyrosine kinase receptor c-Met, a 190-kDa protein consisting of a 45-kDa -chain and a 145-kDa -chain (82). Ligand
binding induces autophoshorylation of tyrosine residues
in the -chain of c-Met, and this leads to association with
proteins containing an SH2 (src homology 2) binding
domain, a PTB (phosphotyrosine binding domain), or an
MBD (Met binding domain). From there a variety of signaling pathways start leading to the pleiotropic functions
exerted by the PRGF-1/c-Met system (412). PRGF-1 stimulates invasion into collagen type I of Src-transformed
human colon cells PC-msrc but not of their parental cells
PC/AA/C1. Src induces tumorigenicity in the PC/AA/C1
cells as well as upregulation of c-Met, but concomitant
activation of Src and PI 3-kinase pathways is necessary
for invasion (123). An autocrine invasion-stimulatory
PRGF-1/c-Met loop has been described after successful
transfection of c-MET-positive rat bladder cells NBT-II
with PRGF-1 (33) or of MDCK(LT) cells with SV40 large-T
antigen inactivating Rb family proteins (257). In the latter
experiments, invasion was scored as e- to f-morphotype
transition, scattering, branching of colonies in collagen
type I, and formation of invasive cancers in nude mice. It
is difficult to interpret the proinvasive activity of PRGF-1
solely in terms of motility stimulation, since activation of
c-Met starts a complex program of invasion, growth, and
survival (264, 399, 411). Such program is not only active in
cancer but also in postnatal mammary gland development
(455).
2. Chemokines and leptin
Chemokines constitute a family of chemotactic cytokines, small (520 kDa) proteins produced locally by injuried or infected tissues as well as by tumors; they have
been implicated in extravasation of cells at specific organ
sites. Chemokines fall into two categories, CXC and CC,
following the position of the first two cysteins being separated or not by another amino acid. At sites of extrava-
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organ into another and, for microorganisms, from one

host into another. Invasive cells mostly perform active
locomotion themselves, and passive transport by helper
cells is exceptional. In the most widely used assays for
invasion, displacement of cells by active migration is a
frequent end-point. For most authors, the difference between invasion and migration lays in the barriers that
cells need to cross to go from one site to another. To
simplify, invasion equals migration through an obstructive
matrix (see Fig. 3). Such matrix can be the natural one or
a more or less complicated mimic of it. For example,
intracellular bacterial movement is analyzed in living
cells, in extracts of cells, or in mixtures of proteins (315).
For vertebrate cells, collagen type I is frequently used
with scores for the number of cells found inside the gel at
the end of the incubation period (427). In assays for
chemotaxis or chemoinvasion, the direction of migration
or invasion is guided by a soluble chemical gradient.
Phagokinesis combines migration and phagocytosis of
substrate-coated particles (2). Migration is not restricted
to invasive cancer cells as it occurs also in normal tissues,
such as the intestinal mucosa, and during wound healing.
This normal migration is mimicked in culture on solid
substrate by wounding of monolayers or by growing cell
populations inside collagen type I, where branching morphogenesis occurs (277). Individual cell motile phenotypes on solid tissue culture substrate are described in
terms of stress fiber assembly or membrane ruffling with
formation of lamellipodia and filopodia (293). There are
no arguments to believe that the locomotory apparatus of
cancer cells is different from that of their normel counterparts. Here also, we suspect that the response to stop
signals is different in cancer cells compared with normal
cells (83). Our actual molecular concept of migration is
that motility factors find their receptor on the cell surface
and stimulate the cell to migrate and to find its way
toward the source of the motility factor. Such factors may
stimulate (positive motility factors) or inhibit (negative
motility factors) migration. Most motility factors are motogens as well as mitogens; they act on cell motility as
well as on growth (145). A major effort is now made to
understand the signaling pathways that link the motility
factor to the cellular response (Fig. 11). We discuss here
selected examples related to recent work done in collaboration with C. Gespach and co-workers (INSERM U 482,
Paris, France). The influence of naturally occurring motlity factors on invasion into collagen type I was analyzed
with human colon cancer cell lines, derived from noninvasive or from invasive lesions and with genetically manipulated MDCK cells, originally derived from normal dog
kidney tubules. Whereas the colon cells may be relevant
for the development of colon cancer, the MDCK cells are
considered as representative of the general cellular locomotive and invasive machinery. To define the participation of molecules in signaling pathways, the effect on
359
360
sation organ-derived chemokines recognize their specific

receptor on cancer cells so determining organ specificity
of metastasis (3). Similar mechanisms operate to direct T
lymphocytes expressing CCR4 into Hodgkin lymphomas
Physiol Rev VOL
where the
rected CC
express at
and CCR7,
83 APRIL 2003
Sternberg-Reed cells produce the T-cell-dichemokine TARC (422). Breast cancer cells
high levels the chemokine receptors CXCR4
and their ligands show peak levels in lymph
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FIG. 11. Schematic of some positive and negative invasion signaling pathways, with signaling and signal transduction
on the top and effector pathways plus cellular responses on the bottom; arrows and arcs indicate activation and
inactivation, respectively; dots and asterisks indicate pharmacological inhibitors (shaded) and transfection with dominant negative constructs (dotted lines), respectively. For detailed description, see section VC. Definitions are as follows:
Akt1 (PKB), murine thymoma viral oncogene homolog 1; AP-1, activator protein 1, transcription factors binding to the
AP-1 DNA binding site; Arp2/3, seven-polypeptide-containing complex participating at actin nucleation; Bad, BCL-2
antagonist of cell death; BCL-2, B-cell CLL/lymphoma 2 protein interfering with normal apoptosis; C3T, Clostridium
botulinum exoenzyme C3 transferase; CaMLCK, calcium-dependent myosin light-chain kinase; CAS, Crk-associated
substrate; Cdc42, cell division cycle 42, a small G protein; COX-2, cyclooxygenase-2; Crk, molecular adhesive containing
Src homology domains, encoded by the avian sarcoma virus oncogene homolog; CtARK, COOH-terminal end of the
-adrenergic receptor kinase; CTN, catenin; ECM, extracellular matrix; ERK (MAPK), extracellular signal-regulated
kinase; FAK, p125 focal adhesion kinase; Grb2, growth factor receptor-bound protein 2 with Src homology domains; G,
a subunit of heterotrimeric G proteins, subscripts indicate isoforms; G, subunit of heterotrimeric G proteins,
subscripts indicate isoforms; JAK2, Janus kinase 2; MAPK (ERK), mitogen-activated (serine/threonine) protein kinase;
MEK (MAPK kinase), dual-specificity protein kinase phosphorylating serine and tyrosine residues; MHC, myosin heavy
chain; MLC, myosin light chain; mTOR, mammalian target of rapamycin; N17Rac1, expressing dominant negative Rac1;
N19RhoA, expressing dominant negative RhoA; Ob-Rb, leptin receptor; p110DN, transfection with the dominant negative
mutant p110a EcoS of PI3-K; PAF, platelet activating factor; PAF-R, PAF receptor; PAK1, p21/Cdc42/Rac1-activated
kinase 1; PAR1, protease-activated receptor 1; PI3-K, phosphoinositide 3-kinase; PKB, protein kinase B; PKC, protein
kinase C; PLC, phospholipase C; PTx, pertussis toxin; Rac, Ras-related C3 botulinum toxin substrate; Raf, serine/
threonine protein kinase encoded by the cellular protooncogene homologous to the viral murine sarcoma oncogene
v-RAF; Ras, small GTPase of the Ras homolog family; Rho, Ras homolog; Rock, Rho kinases; RTK, receptor tyrosine
kinases; Shc, transforming proteins containing Src homology (SH) domains; Sos, son of the sevenless, Drosophila,
homolog; guanine nucleotide exchange factor; Src, tyrosine protein kinase encoded by the cellular protooncogene
homologous to the viral Rous sarcoma oncogene v-SRC; STAT3, signal transducer and activator of transcription 3; Tiam1,
T-cell invasion and metastasis 1, Rac GEF; TKI, tyrosine kynase inhibitor; TXA2, thromboxane A2; TXA2-R, TXA2
receptor; WASP, Wiskott-Aldrich syndrome protein. [Data from Collard (79), Empereur et al. (123), Schwartz (357), Jou
and Nelson (193), Kotelevets et al. (217), Coughlin (89), Attoub et al. (11), Emami et al. (122), Faivre et al. (128),
Marinissen and Gutkind (254), Rodrigues et al. (338), and Nguyen et al. (289).]
CANCER INVASION
3. Trefoil factors
Trefoil factors are protease-resistant peptides with a
three-loop trefoil structure (401). The human trefoil peptide family has three members, namely, pS2 (TFF1, originally identified as an estrogen-inducible gene in a breast
cancer derived cDNA library), spasmolytic polypeptide
(SP; TFF2), and intestinal trefoil factor (ITF; TFF3). They
are produced in the mammalian gastrointestinal tract by
mucus-secreting cells, and they participate at the maintenance of the mucosal barrier through direct interaction
with the mucins without a defined molecular receptor
identified (348, 405, 449). The latter function was confirmed by the findings that transgenic mice overexpressing pS2 in the jejunum were protected against indomethacin-induced mucosal damage (324) and that mice lacking
ITF died of severe colitis upon mild injury (261). TFF
inhibits apoptosis (397) and stimulates migration in
wound healing models (198) as well as branching morphogenesis of human mammary cells MCF-7 (223).
Clearly, TFF are motility factors, although this is not their
only invasion-associated function. The mpS2 null mice
develop antropyloric adenomas and intramucosal carcinomas but no invasive carcinomas, leading to the concluPhysiol Rev VOL
sion that mpS2 acts as a tumor-suppressor but not as an

invasion-suppressor gene (232). Accordingly, TFF profiles
are the same in the more invasive diffuse type compared
with the less invasive intestinal type of gastric cancer
(242). TFF3 causes tyrosine phosphorylation of -catenin,
reduces cell-cell adhesion, and stimulates migration
(239); an intact E-cadherin is necessary for the promigratory response to TFF3 (119). Transfection of pS2 results
in invasion of MDCKts.src and HCT-8/E11 cells into collagen type I, and the invasion is dependent on PI 3-kinase,
phospholipase C, and protein kinase C (122). In contrast
to invasion resulting from addition of extrinsic TFFs, the
invasion of pS2 transfectants is independent of RhoA and
follows the COX/TAX2-R/PLC pathway (338). The earlier
stage cell lines PC/AA/C1 and MDCK do not respond to
TFF by invasion and scattering, in contrast to the further progressed stages represented by PCmsrc and
MDCKts.src (122).
4. Bile acids
Bile acids are implicated in colorectal carcinogenesis
as evidenced by epidemiological and experimental studies (285, 332). The invasion-stimulatory effect of some bile
acids has recently been demonstrated (97). In the collagen type I assay, lithocholic acid, chenodeoxycholic acid,
cholic acid, and deoxycholic acid stimulated invasion in
SRC-transformed PCmsrc and in RhoAV14 (mutant RhoA
deaf to GTPase)-transformed MDCKT23 cells, and
HCT-8/E11 cells originating from a sporadic tumor, but
were ineffective in premalignant PC/AA/C1 and MDCKT23
cells. This is in line with the finding that lithocholic acid is
involved in invasion-associated cellular activities, namely,
induction of cyclooxygenase-2 (COX-2), secretion of
MMP-2, and migration of colorectal cancer cells (151,
161). In HCT8/E11 cells, cellular invasion was associated
with activation of the Rac1 and RhoA GTPases and expression of the farnesoid X receptor, recently identified as
a bile acid receptor (377, 437, 452). Pharmacological inhibitors revealed that bile acid-stimulated invasion was
dependent on the RhoA/Rho-kinase pathway and the signaling cascades using protein kinase C, mitogen-activated
protein kinase, and COX-2. The cellular activity that correlated best with stimulation of invasion was haptotaxis,
directed migration of cells following a semi-solid gradient
of matrix molecules.
5. Platelet activating factor
The negative invasion signaling pathways are illustrated by the alkyl phospolipid platelet activating factor
(PAF). PAF was considered as a modulator of invasion
because it is implicated in inflammatory bowel disease, a
condition frequently associated with colorectal cancer
(339). Specific tissue-type PAF-R are present in human
intestinal epithelial cells, both normal and cancerous
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nodes, lungs, liver, and bone, all frequent sites of breast

cancer metastasis (280). The cancer cells respond to
these chemokines in assays for chemoinvasion or chemotaxis in a specific manner as evidenced by inhibition
through receptor-specific neutralizing antibodies. Similarly, CXCR4 receptors on ovarian cancer cells may influence their spread in the peritoneum (360). Another chemokine possibly implicated in breast cancer is RANTES
(13). Chemokine receptors signal via Janus kinase/signal
transducers and activators of transcription (JAK/STAT),
as exemplified by the Ob receptor for leptin (see Fig. 11)
or via the Ras/Raf/MAPK pathway. Leptin is the hormone
that regulates food intake and energy consumption (136).
It is produced mainly by adipose tissue but also by digestive epithelia. Leptin stimulates invasion into collagen
type I of MDCKts.src transformants at 40C and of the
human colon cancer cell lines HCT-8 and LoVo (11). In
contrast to most other stimulators of invasion, leptin also
acted on early stage cell types, such as PC/AA/C1 and
MDCK. All these cells do express the leptin Ob-R receptor, a member of the class II cytokine group receptors
(396). For signaling, Ob-R oligomerizes with itself and
activates the JAK-2/STAT pathway (41, 179). This signaling pathway was confirmed through inhibition of leptinstimulated invasion by pharmacological inhibitors of
JAK2, PI 3-kinase, mTOR kinase, and protein kinase C
(Fig. 11). The participation of the Rac/Rho signaling was
evidenced by the fact that cells expressing dominant negative mutants of RhoA and Rac1 were no longer sensitive
to stimulation of invasion by leptin (11).
361
362
6. N-cadherin and motility signaling

In section III, N-cadherin is described as an invasion
promoter. There are arguments to accept that N-cadherin
functions in a motility pathway. The upregulation of Ncadherin in mesodermal cells during gastrulation suggests, indeed, a role in migration for this member of the
cadherin transmembrane cell-cell adhesion family (165).
In retinoblastoma cells, antibodies functionally neutralizing N-cadherin block invasion and migration (420). One
possible mechanism of action is within a complex of
N-cadherin with FGF-R and neural cell adhesion molecule
(N-CAM) (73). Loss of N-CAM from the complex stimulates metastasis from pancreatic -cell tumors, possibly
through alteration of FGFR regulated cell-matrix adhesion. The HAV sequence in the fourth extracellular domain of N-cadherin interacts with the HAV sequence in
FGFR, activating a signaling pathway that leads to neurite
outgrowth (112). From the activated FGFR multiple signaling pathways may start, leading either to an increase in
motility via activation of diacylglycerol (291) or to an
increase in MMP-9 production via activation of the mitogen-activated protein kinase pathway (167). The HAV containing 69-amino acid portion of the fourth extracellular
domain of N-cadherin is necessary and sufficient to promote both e- to f-morphotype transition and increased cell
motility (209). The juxtamembrane domain of N-cadherin
regulates neurite outgrowth (336). p120ctn (403) and the
nonreceptor tyrosine kinase Fer are potential regulatory
molecules associated either directly or indirectly with the
Physiol Rev VOL
juxtamembrane domain of cadherins (340). P120ctn may

influence the activity of Rho family GTPases, thereby
influencing motility and invasion (5, 301). The increase of
N-cadherin expression and/or the shift in p120ctn isoform
expression can disrupt the delicate balance between cadherins, p120ctn and Rho family GTPases, leading to a
change in morphology and increased motility and invasion. Trojan peptides, designed to interfere with the juxtamembrane domain of N-cadherin, release Fer kinase
from N-cadherin. This is accompanied by an accumulation of Fer kinase in the integrin complex and results in
inhibition of neurite outgrowth (10). Whether Fer kinase
plays a role in N-cadherin-mediated invasion is presently
unknown. As with other molecules associated with invasion pathways, motility is not the only activity affected by
changes in N-cadherin. The latter serves also heterotypic
adhesion of cancer cells with N-cadherin expressing stromal cells such as myofibroblasts (166, 409, 425). TGF-1
causes a RhoA-dependent e- to f- morphotype transition
of mouse mammary cells, and this transition is accompanied by a decrease in E-cadherin expression and an increase in N-cadherin expression (38, 121, 212). In cells in
which the apoptotic function of TGF- is abrogated
through activation of Ras or of receptor tyrosine kinases,
TGF- may upregulate Snail and so downregulate E-cadherin and stimulate invasion (399). A complete understanding of the downstream signaling pathways is needed
to elucidate the crucial mechanisms by which N-cadherin
stimulates invasion in tumors and in embryonic development.
7. Rac/Rho/Cdc42/actin dynamics and motility
Many forms of invasion mentioned above are dependent on the small GTPases Rho, Rac, Cdc42, and Ras,
which are essential for the control of the actin assembly/
disassembly equilibria regulating cell movement. This
complex received major attention from students of cancer invasion and motility (11, 79, 203, 293). Through their
multiple target proteins, the function of these GTPases is
not restricted to migration but also involves adhesion and
proliferation (243). Whereas Rac controls protrusion of
lamellipodia and forward movement, Cdc42 maintains
cell polarity and Rho mediates the cell substrate adhesion
needed for migration and stabilizes microtubules that are
oriented toward the leading edge. Evidence for the participation of Rho GTPases at invasion comes from 1)
pharmacological inhibition by ADP-ribosylation, e.g., with
the Clostridium botulinum exoenzyme C3 transferase; 2)
transfection of cells with dominant negative mutants of
RhoA or Rac or with inhibitors of RhoA, e.g., RhoD, or
with dominant constitutive forms of Rho and Rac; and 3)
measurements of active Rho and Rac after stimulation of
invasion (11, 122). The role of RhoA is confirmed by
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(217). PAF prevented invasion into collagen of MDCKts.src

at 35C and of colon cancer cells (PCmsrc) stimulated,
respectively, by activation of SRC and by PRGF1. The
specificity of PAF signaling was shown through restoration of invasion by the PAF-R antagonists WEB2086 and
SR27417 (Fig. 11). PRGF1-mediated phosphorylation of
p125 FAK is blocked by PAF. PAF-dependent pathways
are pertussis toxin sensitive and insensitive to rapamycin,
pointing to a role for trimeric G proteins. Interestingly,
invasion stimulated by bile acids or by TFF is not inhibited by PAF. The serpentine PAF receptor is a G proteincoupled receptor, the largest family of cell surface receptors (128, 254). PAF-R activation impairs invasion, e.g.,
stimulated by Src or leptin, via Gi13 and Go. G
dimers, interacting with multiple signal transduction pathways for growth and survival (359), are at the positive
side of invasion pathway. Pertussis toxin, the A protomer
of which ADP-ribosylates cysteine residues of membrane
Go/i subunits, blocks the heterotrimeric G complex
in the inactive GDP-bound state and prevents dissociation
of G and G subunits. Pertussis toxin interferes with
invasion-negative signaling, e.g., via the PAF-R as well as
with invasion-positive signaling, e.g., via c-Met.
CANCER INVASION
induction of transmesothelial invasion of MM1 rat cells in

vivo and in vitro, after transfection with cDNA encoding
dominant active ROCK; here, invasion was counteracted
by the specific ROCK inhibitor Y-27632 (183). The effects
of RhoA on cell migration can be counteracted by RhoD
(414) and by cGMP-dependent protein kinase (351). The
latter activity is mediated by mDia, Rho effectors known
as the diaphanous-related formins, and does not necessitate Rho kinase (314). Cell type specificity and substrate
dependence of invasion pathways are illustrated by the
Rac GEF Tiam1 (T-cell invasion and metastasis) (272,
347). In lymphoma cells and in fibroblast-like cells, Tiam1
promotes invasion, hence its acronym. In epithelial cells,
opposing effects were seen on E-cadherin-mediated cellcell adhesion and migration, with invasion-inhibitory signals from contact with fibronectin or laminin and invasion-stimulatory signals from collagen.
8. PI 3-kinase
9. Host actin-mediated bacterial movement

Invasive bacteria exploit the host cells machinery to
move inside the cytoplasm and to spread intercellularly
(86, 371). Shigella uses its IcsA protein to recruit and
activate N-WASP, leading to recruitement of the Arp2/3
complex and actin polymerization that forms the comet
tail for bacterial movement. The Listeria ActA directly
recruits Arp2/3, mimicking proteins of the WASP family.
When a hybrid ActA protein is tethered to the cell wall of
the unrelated bacterial species S. pneumoniae, these bacteria do polymerize actin, form the typical actin comet
Physiol Rev VOL
tails, and move in Xenopus extracts (370). Moreover,

expression of ActA in the nonpathogenic nonactin polymerizing L. innocua confers to this nonmotile bacterium
the capacity of actin-based motility in Xenopus egg extracts (214). In all the above-mentioned cases, the invaders seem to use very similar host signal transduction
pathways.
D. Proteolysis
Proteolysis occurs in cascades, where proenzymes
are proteolytically cleaved before they act on their own
substrate. As extensively reviewed by others (7, 120, 192,
267, 274, 297, 443), such cascades participate at invasion
in a number of ways: breakdown of extracellular matrix
to create routes for the migration of invaders; release and
activation of survival and motility factors from the ECM;
cleavage of cell surface receptors that act as signal transducers in invasion pathways; and ectodomain shedding of
proinvasive fragments from transmembrane receptors.
Most of these proteinases belong to the urokinase-type
plasminogen activator system, to the MMP (34), or to
cysteineproteinase family (389).
1. Matrix degradation
Proteolytic degradation of the extracellular matrix is
a crucial activity of invasive cells. The participation of
enzymes to invasion-associated matrix degradation is not
limited to protein cleavage but also involves degradation
of glycosaminoglycans (434). To leave the confines of the
epithelium, cancer cells need to penetrate the basement
membrane with the help of MMPs that degrade collagen
type IV and other elements of this matrix (267). The
expression of proteinases participating in invason is sensitive to multiple signals. Proenzymes are processed to
active enzymes in cascades of proteinases. Interaction
with natural inhibitors, such as tissue inhibitors of metalloproteinases (TIMPs) and plasminogen activator inhibitors (PAIs), is another level at which proteinase activities
are regulated. These inhibitors are fine-tuned by switching
from an inactive to an active form. Many proteinases that
participate in invasion are secreted by stromal cells and
find their receptor on the cancer cells as exemplified by
stromelysin-3 (MMP-11) in breast cancer (20). Focalization at invadopodia is another way to regulate the lytic
activity of cancer cells (78, 84). Interestingly, there exists
evidence that MMPs might also favor cancer cell survival
in the stromal environment (50).
2. Thrombin
Some proteases are signaling molecules, since they
cleave and so activate members of the family of protein-
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The inhibitors of PI 3-kinse, wortmannin and

LY294502, interfere with most forms of invasion. It is,
therefore, tempting to speculate that this kinase is
pivotal for positive invasion signaling or that it is crucial for the invasion-related cellular activities that determine the cells response to extrinsic and intrinsic
modulators. Activation of PI 3-kinase- promotes invasion and growth factor-independent survival (16). Human colorectal cancer cells HCT-8/E11 expressing constitutively active, membrane targeted PI 3-kinase- (PI
3-kinase--CAAX, carrying the Ras farnesylation signal)
invaded into collagen and resist serum-withdrawal induced apoptosis, in contrast to cells expressing its
catalytically inactive counterpart (PI 3-kinase--KRCAAX). Both invasion and survival were abolished by
the PI 3-kinase inhibitor LY294002. Whereas the constitutively activated PI 3-kinase induces invasion, the
dominant negative (DN) PI 3-kinase p110 catalytic
subunit abrogates invasion. Two major signals emerge
from PI 3-kinase, namely, activation of PKB via phosphoinositides (Fig. 11) and protein phosphorylation activating mitogen-activated protein kinase (43).
363
364
3. E-cadherin ectodomain shedding

Release from the cell surface of protein fragments in
an autocrine or in a paracrine way constitutes a new
mechanism by which proteinases stimulate invasion (295,
296, 343, 445). During the spontaneous turnover of Ecadherin, a stable 80-kDa fragment (sE-CAD; s, for solu-
ble) is released into the medium. This process can be

mimicked by treatment of cells with proteinases, including stromelysin-1, matrilysin (MMP7), and plasmin (Fig.
12). Apoptosis is also accompanied by the production of
sE-CAD (382). The 80-kDa sE-CAD inhibits the function of
the E-cadherin/catenin complex in a paracrine manner,
inducing invasion of cells into collagen type I and hampering their homotypic, E-cadherin-dependent cell-cell
adhesion. Because these phenomena can also be evoked
by decapeptides homologous to the HAV region of the
first extracellular domain of E-cadherin, and because peptides with a mutation in the HAV sequence failed to do so,
we accept a crucial role for the HAV sequence. How the
sE-CAD signal is received by the cell, how the signal is
transduced, and how the cell responds to become invasive remains to be elucidated.
4. Proteinases in invasion of microorganisms
Bacterial proteinases figure in textbooks as virulence
factors. The role of cysteine proteinases in tissue invasion
has been well documented for the amoebic parasite E.
histolytica (329). The purified proteinases degrade components of the extracellular matrix, including fibronectin,
laminin, and collagen. Cysteine proteinases are primarily
responsible for the cytopathic effect, as observed in an in
vitro assay of virulence. Mutants of E. histolytica strain
HM-1, which are deficient in both proteinase expression
and cytopathic effect, have been identified. The in vitro
cytopathic effect correlates with the early steps of invasion in animal models in which the intestinal epithelial
cells separate before making direct contact with trophozoites, presumably as a consequence of proteolytic degradation of the extracellular matrix.
FIG. 12. E-cadherin ectodomain shedding

resulting in the formation of an invasion-promoting sE-cadherin fragment. For detailed
description, see section VD. [Adapted from
Noe et al. (294), with data from Steinhusen et
al. (382), Vallorosi et al. (418), and Brancolini
et al. (58).]
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ase-activated receptors (PAR). Such receptors can be activated through a soluble ligand (TRAP, thrombin receptor-activating peptide) or through tethering of an internal
ligand by a proteinase (103, 139). Thrombin cleaves the G
protein-coupled receptor PAR to influence many cellular
activities, including platelet aggregation, inflammation,
chemotaxis, mitogenesis, apoptosis, and angiogenesis
(89, 195). Biologically functional thrombin receptors were
found on various types of cancer cells from various species (447). Preferential expression of thrombin receptors
in highly invasive and metastatic cancers led some workers to conclude that this receptor was on the invasionstimulatory pathway, and this was supported by the reduction of invasion by introduction of thrombin receptor
antisense cDNA (126). The latter authors did, however,
not evaluate the effect of added thrombin on invasion. In
others experiments, activation of PAR1 with thrombin or
with the peptide agonist SFLLRN inhibited chemotaxis of
mammary cancer cell lines MDAMB231 through an Gi/PI
3-kinase-dependent pathway (195). In recent experiments, thrombin or its peptide agonist inhibited invasion
of human colon cancer cells into collagen type I (128).
PAR1 is coupled to the pertussis toxin-sensitive Go/i
proteins, activating a negative invasion pathway (Fig. 11)
as evidenced by tranfection with activated Go/i subunits.
In contrast, G subunits are on the positive signaling
pathway of various stimulators of invasion.
CANCER INVASION
VI. CONCLUSIONS AND PERSPECTIVES
Physiol Rev VOL
Invasion and metastasis depend on the collaboration

between the invaders and cells from the host, exemplified
by myofibroblasts, endothelial cells, leukocytes, and osteoclasts. Remarkable paradigms of how invaders divert
the host cells machinery are found in cellular microbiology, a new discipline analyzing the molecular interaction
between microorganisms and vertebrate cells. The scenario of the cross-talk between cancer cells and host cells
comprises the release by the cancer cells of cytokines that
stimulate the host cells to produce proinvasive molecules
recognizing specific receptors on the cancer cell and so
initiating invasion-associated cellular activities. Such
cross-talk explains organ specificity of metastasis either
through specific homing and extravasation or to specific
survival and growth of the cancer cells at the site of
extravasation.
A major challenge consists of tracing the molecular
pathways from the extracellular signal to the receptor to
the signal transduction and finally to the cellular response
that is crucial for the alteration of the invasive phenotype.
Attention has been paid mainly to intracellular pathways.
Molecular interactions in the extracellular compartment,
although less well delineated, certainly deserve more attention.
In this review we have tried to categorize molecular
pathways in accordance with invasion-associated cellular
activities, namely, cell-cell adhesion, cell-matrix adhesion
and ectopic survival, migration, and proteolysis. This
strategy might have some didactic value. It is, however,
obvious that most genetic, epigenetic, or pharmacological
manipulations influence more than just one of these activities. Such lack of selectivity is well understood since,
even in case of ligand specificty, signals from activated
receptors rapidly branch to follow pathways toward different cellular responses. Moreover, there exists extensive cross-talking between elements of signaling pathways leading to complex networks implicating multiple
short circuits. From the list of molecules with documented implication in invasion pathways, we would suggest a selection for further study on the basis of their
redundancy in several invasion pathways, as exemplified
by small GTPases of the Rac/Rho family and by PI 3-kinase, and of their pivotal function in switches from invasion positive to invasion negative pathways, as exemplified by double-edged swords like cadherin/catenin
complexes and trimeric G proteins. The ultimate goal of
such study is the restoration, through manipulation of
positive and negative invasion pathways in cancer cells or
in host cells, of the restriction that normal adult organisms impinge upon invasion.
We thank G. De Bruyne for preparing the illustrations.
Address for reprint requests and other correspondence:
M. Mareel, Laboratory of Experimental Cancerology, Dept. of
Radiotherapy and Nuclear Medicine, Ghent University Hos-
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Invasion has broadened its scope from cellular pathology to molecular cell biology and cellular microbiology. Although it is the cause of cancer malignancy, invasion is not cancer cell specific because it occurs in many
other pathological and also in normal situations. What
makes cancer cell invasion the hallmark of tumor malignancy? Progression from noninvasive lesions toward invasive carcinomas can be observed in tumors such as
colon cancers emerging in polyps and in cancer of the
uterine cervix. Many cancers display no preinvasive stage
and suggest an almost synchronic start of aberrant growth
and invasion. One hypothesis is that the acquisition of
invasive potential is accompanied by switching on of a
whole program, implicating occupation of new tissue territories, ectopic survival, and clonal growth in the new
territories. Understanding of this program in more detail
may lead to a more refined grading and staging of tumors
and a tailor-made therapy.
More than 100 genes have been identified as tumorpromoter or tumor-suppressor genes, and the products of
these genes belong to various protein superfamilies, such
as cytokines, cell surface receptors, signal transducers,
and transcription factors. Several genetic changes are
needed for full tumor development, and their nature and
order may vary even within a single type of cancer. RNA
and protein microarrays demonstrate bewildering spectra
of differences between normal tissue and noninvasive or
invasive cancers derived therefrom. New algorithms are
needed to translate these arrays into individual tumor
phenotypes that are molecularly, biologically, and clinically relevant. There is no convincing evidence to further
support the idea that oncogenes and tumor-suppressor
genes are implicated in growth disturbance and that they
differ from genes promoting or suppressing differentiation, invasion, or ectopic survival. Phenotypic changes
relevant for acquisition of invasion may be the consequence of changes in different genes, and a single gene
may be implicated in several tumor progression-associated phenotypes, which even may have opposite effects
on invasion. Metastasis is based on a multistep process of
invasion and, as a consequence, only invasive cancer do
metastasize. Conversely, invasive tumors largely differ in
metastatic ability. The number of candidate metastasis
genes that are capable to specifically change the metastatic phenotype of invasive tumors is limited. What
makes an invasive cancer metastatic still remains an open
question. Comparison of microorganisms, embryonic
cells, normal adult cells like leukocytes, and cancer cells
suggests the following hypothesis. Invasion is an evolutionary conserved mechanism of cell-cell interaction; in
adults, invasion is subject to tissue restrictions, compared
with embryonic organisms, and these restrictions seem to
be disturbed during tumor progression.
365
366
pital P7, De Pintelaan 185, B9000, Ghent, Belgium (E-mail:

marc.mareel@rug.ac.be).
20.
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Clinical, Cellular, and Molecular Aspects of Cancer

Invasion
Marc Mareel and Ancy Leroy
Physiol Rev 83:337-376, 2003. doi:10.1152/physrev.00024.2002

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Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is
published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda
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Physiol Rev

83: 337376, 2003; 10.1152/physrev.00024.2002.

Clinical, Cellular, and Molecular Aspects

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0031-9333/03 $15.00 Copyright 2003 the American Physiological Society

MARC MAREEL AND ANCY LEROY

Physiol Rev VOL

II. CANCER PATHOGENESIS

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Cancer is malignant because cancer cells invade into

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noma in situ. There has been a long debate about whether

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differentiation. Attention is paid also to the host cell

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FIG. 1. Schematic representation of genetic,

Physiol Rev VOL

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noma metastases may resemble the organized epithelial

A. The E-cadherin Gene CDH1,

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and occur in varying orders so that it is difficult to ascribe

MARC MAREEL AND ANCY LEROY

FIG. 2. E-cadherin promoter with

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sition of an e-morphotype, and loss of invasiveness. The

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colon cancer HCT-8 cells, coined HCT-8/E11 for clonal

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the E-cadherin promoter are presented in Figure 2. Note

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sion promoter role of N-cadherin. Immunohistochemical

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D. The -catenin Gene CTNNB1,

-Catenin, like the other catenins, was described first

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-Catenins are considered to be essential elements of

invade, the former as epithelioid strands and the latter as

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showed deletions of 234 760 bp, each of which included

MARC MAREEL AND ANCY LEROY

E. Kinases and Phosphatase Genes, Invasion

come an oncogene. Such activating mutations are found

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adhesion (196, 201, 310). In normal mesenchymal cells

(75). Interestingly, the SLC-44 cells and its derivatives had

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human cancers, including kidney (356), thyroid, pancreas,

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FIG. 4. Genetic manipulation of apparently

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herin. The same tranfections counteracted invasion also

no distinction can be made between the acquisition of

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plcB), the two others (inlA and inlB) form a distinct

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During normal embryonic development, spatiotemporal activation and inactivation of invasion-promoter

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of this review is on the continuous molecular cross-talk

B. Myofibroblasts: Stimulators of Invasion

Blood vessels and lymph vessels provide tumors with

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