Cancer Biology & Therapy

ISSN: 1538-4047 (Print) 1555-8576 (Online) Journal homepage: https://www.tandfonline.com/loi/kcbt20

Molecular theory of cancer

Mikhail V. Blagosklonny

To cite this article: Mikhail V. Blagosklonny (2005) Molecular theory of cancer, Cancer Biology &
Therapy, 4:6, 621-627, DOI: 10.4161/cbt.4.6.1818

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Published online: 05 Apr 2005.

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[Cancer Biology & Therapy 4:6, 621-627, June 2005]; ©2005 Landes Bioscience

Molecular Theory of Cancer

Review

Mikhail V. Blagosklonny ABSTRACT

Correspondence to: Mikhail V. Blagosklonny; Cancer Center; Ordway Research The mutation theory of cancer was always confronted by alternative (vitalistic)
Institute; 150 New Scotland Avenue; Albany, NewYork 12208 USA; theories, which insist that cancer (like life itself) cannot be reduced to molecular
Email: blagosklonny@oncotarget.com interactions. In fact, the most fundamental feature of the somatic mutation theory of
Received 03/14/05; Accepted 05/05/05 cancer is that it is a molecular theory, meaning that all the complexity of cancer on any

E .
Previously published online as a Cancer Biology & Therapy E-publication:
level (e.g., tissue) can be explained on the molecular level. To emphasize the essence of
http://www.landesbioscience.com/journals/cbt/abstract.php?id=1818

UT
mutation theory, cancer-causing mutation can be defined as any (a) molecular event that
is (b) somatically inheritable and (c) selectable (e.g., provides selective advantage in
KEY WORDS restrictive/carcinogenic conditions). Here I review molecular (somatic mutation) theory

RIB
and its alternatives and discuss that molecular interactions can completely explain
cancer, carcinogenesis, mutation, oncogene, complex tissue phenomena such as benign tumors and stroma initiated tumorigenesis.

IST
tumor suppressor In addition, molecular theory predicts extragenetic somatic heredity in cancer (e.g., post-

ACKNOWLEDGMENTS
translational protein modifications that initiate and are supported by positive feedback
loops) and also explains the relationship between selection for resistance, hallmarks of

D
cancer and genetic instability. From molecules to cells to the organism, this review discusses
I thank Bert Vogelstein for suggestions and
how somatically heritable molecular alterations (genetic, epigenetic and extragenetic)

OT
encouragement.
alter translation of cellular signals, resulting in resistance to growth inhibition and apop-
tosis, that is manifested as secondary hallmarks of cancer (metastasis, angiogenesis and
ON
immortality) and, finally, as the amazing ability of some cancer cells such as canine trans-
missible sarcoma to 'live in a wild' like unicellular mammalian species.
.D

SOMATIC MUTATION THEORY AND ITS ALTERNATIVE

CE

Cancer arises from a stepwise accumulation of genetic and epigenetic changes in

IEN

oncogenes and tumor suppressors that liberates neoplastic cells from the homeostatic
mechanisms that govern normal cell proliferation.1–4 The mutation theory of cancer
SC

was always challenged by alternative notions that cancer cannot be reduced to molecular
interactions. Recently, it has been suggested that one alternative theory is on a road of
BIO

acceptance, replacing the mutation theory to explain the complexity of cancer on tissue
levels.5 As suggested, carcinogenesis represents a problem of tissue organization and
“somatic mutation theory should be dropped and replaced”.6 Under the pressure of the
alternative theory, it has been acknowledged that somatic mutations do not explain
ES

the complex biology of human tumors, simply because tumors are complex tissues.5
If mutations cannot explain cancer, then what can? The alternative theory does not
ND

offer any molecular mechanism. Instead, it insists that the somatic mutation theory
is contradicted by evidence.5,6 Here I discuss that “evidence” may contradict only to
LA

misinterpretations of somatic mutation theory not to the theory itself.

DO ALTERNATIVE THEORIES ACTUALLY CONFRONT SOMATIC MUTATION THEORY?

05

1. The first premise of Tissue Organization Field Theory of Cancer (TOFT) is that
20

proliferation is the default state of all cells. This simply means that all normal and cancer
cells always proliferate unless they are forced not to proliferate.6 This premise neither
©

contradicts nor supports the mutation theory, because the mutation theory is not about
whether it is natural to proliferate. In analogy, although automobiles exist to run, this is
hardly their ‘default state’. At least, engine should be ignited and breaks should be released.
Similarly, cells have breaks of the cell cycle such as Rb, for instance.3,7,8 The mitogenic
signal inactivates Rb by phosphporylation. Thus, mitogens ‘release the break’ of the cell
cycle. And breaks (e.g., Rb, p53, p27) are mutated in cancer.3,8 As another example, TGFβ
(via complex pathways) de phosporylates Rb, thus arresting cell cycle. Cancer cells are

www.landesbioscience.com Cancer Biology & Therapy 621

 Molecular Theory of Cancer
resistant to (or even stimulated by) TGFβ, because of mutations
in oncogenes and tumor suppressors.9–14 So, the mutation theory
describes on molecular levels what TOFT suggests as premise.
2. According to TOFT, normal cells proliferate faster than cancer
cells,6 allegedly contradicting to mutation theory. Again, the mutation
theory is not about who proliferates faster, even though, in growth
limiting conditions that repress normal cell proliferation, cancer
cells do proliferate faster. Resistance to antimitogens such as TGFβ
(not the speed of proliferation at undefined condition) is a hallmark
of cancer.3
3. TOFT is concerned that the number of mutations needed to
make cancer is improbably high.6 These concerns are not justified.
According to the mutation theory, just a few cooperating mutations
in oncogenes and tumor suppressors can transform cells. 15–17
Furthermore, one single mutation may be sufficient. For example,
Bcr Abl causes chronic myelogenic leukemia,18 and inducible c myc
causes experimental tumors.19 Even cancer without mutations (e.g.,
teratomas and choriocarinomas) is not a contradiction. These tumors
are formed by misplaced embryonic and placental cells, with altered
expression of hundreds of oncogenes and tumor suppressors
(silenced or induced by epigenetic mechanisms) in comparison with
adult tissues. In comparison with adult tissues, such displaced
embryonic cells are epigenetically mutant.
4. According to TOFT, spontaneous regression of tumors contra-
dicts the mutation theory. Although spontaneously regressing tumors
are (unfortunately) rare, they actually concur the mutation theory.
Mutations per se do not need to be reversible; instead cells carrying
these mutations can go extinct (undergo apoptosis or senescence).
While rendering cells fit to one condition, oncogenic mutation
renders cells unfit to another condition. Spontaneous regressions are
rare in advanced tumors with multiple genetic alterations, but may
happen often in initial stages of cancer progression. Perhaps many
pre cancer cells are eliminated by oncogene induced apoptosis and
senescence.20
5. According to TOFT, pathogens and carcinogens disrupt the
normal biological interactions between epithelial cells and stroma.
This does not overturn the mutation theory. Yes, stroma plays a
critical role in tumor development. In mutation theory, either
epithelial cells, or stromal cells or both can be genetically and epige-
netically altered.21,22 Also, cells reciprocally influence each other be
producing and secreting molecules (such as growth factors).
In summary, the essential difference between two theories is that
the mutation theory provides molecular mechanisms, whereas
TOFT does not. Instead, TOFT states tissue phenomena cannot be
reduced to molecular events. Furthermore, according to TOFT, the
‘problem’ of the mutation theory is the dependence on molecular
biology, which has also set its own self fulfilling terms for therapy:
hitting molecular targets.5 Actually, targets for all drugs including
standard chemotherapy are molecular: tubulin, topoisomerases and
estrogen receptors, for instance. Non molecular targets do not exist.
The strength of the somatic mutation theory is precisely its ability to
suggest new therapeutic approaches and molecular targets.23-26
MOLECULAR THEORY: ESSENTIAL PRINCIPLES
First principle is that all complex cancer phenomena can
be reduced to molecular events. For example, phosphorylation
of Rb, ubiquitination of p53 and GTP binding of Ras result in
inactivation of Rb and p53 tumor suppressors and activation of Ras
oncoproteins. Similar phenotypic effects may be caused by
622 Cancer Biology & Therapy
A B C
Figure 1. Extra-genomic somatic heridity (positive feedback loop).
(A) Wild type kinase gene produces inactive kinase (shown as empty
shape). (B) Genetic mutation results in constantly-activated kinase (shown as
blue shape). (C) Extra-genetic 'mutation'. Wt gene produces inactive kinase.
To be activated, kinase needs to be phosphorylated (p). Then an active
kinase phosporylates and activates newly synthesized kinases.
This autoactivation can be maintained in daughter cells. Although proteins
cannot replicate, their modification can and, therefore, can be somatically
inherited, if modifications are maintained by a positive feedback loop.
Whereas negative feedback loops keep a cell under control,115 positive
feedback loops (as suggested here) may provide a means for extra-genetic
inheritance.
alterations in the DNA sequence (genetic mutations) for Rb, p53
and Ras.4,8,27,28 Thus, molecular alterations can be transient
(e.g., phosphorylation of Rb) or stable and, therefore, heritable
(e.g., loss of Rb). For cancer, molecular alterations must be heritable.
In somatic cells, mechanisms of heredity are not necessarily genetic.
Such epigenetic alterations include DNA metylation, histone
deacetylation and alterations in chromatin related proteins.29–33
Recently, a new epigenetic mechanism was uncovered, namely
silencing of genes by microRNA. 34,35
There may be another (so far poorly recognized) mechanism
of heritable somatic alterations in cancer, in addition to genetic
and epigenetic alterations. This is extra genetic somatic heredity.
It could be inheritable only in somatic cells. Although proteins
cannot duplicate, their modifications (e.g., phosphorylation) can be
reproduced (Fig. 1). As a peculiar example, prion can force a normal
protein to adopt prion conformation, thus reproducing itself.36 In
general, if a modified molecule accelerates its own modification
(positive feedback), then this provides a means for extra genetic
somatic heredity. A positive feedback may involve kinase A that
activates kinase B that in turn activates kinase A. Even simpler,
kinase activates itself (Fig. 1). Or, transcription factor may trans
activate itself. Once a positive feedback loop is established, it will be
maintained. Positive feedback loops are recognized in maintenance
of differentiated phenotypes, for instance.37,38 Mitogens, mitogen
activated pathways and transcription factors can form feedback
loops. 39–43 As an example of a positive feedback loop, growth
factors (GF) activate Ras, whereas Ras can induce autocrine GF.44
Via positive feedback loops, GF may stimulate their own production
(Fig. 2) and/or activate autoregulatory kinases.45 Such positive
feedback loops may play role in the epithelial mesenchymal
transition.12,46,47 Importantly, feedback loops can be initiated by
external stimuli: GF and stresses.48 Hypoxia, radiation, cytotoxic
agents and GF activate numerous mitogen activated pathways,
anti apoptotic factors and induce secretion of GF.49–54 Extra
genomic alterations can explain observations that were previously
2005; Vol. 4 Issue 6
 Molecular Theory of Cancer
Figure 2. A feedback loop: autocrine growth factor (GF) activates its own
transcription and secretion.
A physiologic inhibitory signals as mitogenic (Fig. 4). For example,
B further driving selection for oncogenic mutations.
Figure 3. Context-dependent translation of ambivalent signaling. Any signaling
molecule and intracellular signaling pathway is ambivalent, causing cycle arrest
or progression, cell death or survival, suppress or promote cancer, depending
on the cellular context. In this particular example: (A) MAPK simultaneously
induces cyclin D1, activating CDK, and CDK inhibitors, causing growth arrest.
(B) When CDK inhibitors are lost (e.g., epigenetic silencing of p16),
MAPK exclusively causes proliferation.
considered as a challenge to the mutation theory. For example,
hydrogen peroxide causes a phenotypic (malignant) conversion
of mammary epithelial cells, persistent even after withdrawal
of peroxide.55 One can envision that peroxide (which activates
multiple intercellular signaling pathways) connects ‘positive
feedback loop’ that then maintains itself. Other examples include
phenotypic transformation by UVC irradiation and its reversal in
low cell density,56 hypoxia induced benign to malignant melanoma
progression57 and the ability of irradiated stroma to initiate cancer.58
For example, irradiated stroma may secrete GF, which in turn
may initiate positive feedback loops in pre cancerous cells. Once
established, such feedback loops can further sustain themselves.
Following cell division, positive feedback loops can ‘reproduce’ (be
inherited by daughter cells). Unlike germline heredity, somatic
heredity can be based on epigenetic alterations in gene expression
and on modifications of proteins (extra genetic alterations). These
modifications just must be self reproducible in daughter cells
following cell division.
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Third premise is that cells bearing oncogenic mutations can be
selected in growth restrictive conditions. For example, growth
inhibitory and cytotoxic factors select cells for resistance to growth
inhibition and/or cell death. This resistance is due to alterations
in oncogenes and tumor suppressors.59–61 During multistage
carcinogenesis, cells are selected for mutations in oncogenes and
tumor suppressors, precisely because these mutations render cells
resistant to apoptosis and growth arrest (oncogenic resistance).
Importantly, any signal molecule (e.g., TGF beta, growth factors and
death receptors, TPA, radiation, cellular kinases and transcription
factors) is ambivalent, thus potentially causing proliferation,
apoptosis, cycle arrest, differentiation, motility and senescence
depending on the cellular context.14, 62–65 For example, mitogen
can induce both cyclin D and p21 (or p16), thus simultaneously
signaling arrest and progression.66, 67 Inactivation of tumor suppressors
(e.g., p16, p53) and activation of oncogenes allow cells to proliferate
in response to signals that otherwise cause growth arrest, apoptosis
or senescence (Fig. 3). Once oncogenic mutation that confer
resistance to cytostatic/toxic agent is acquired, cell can translate
cells with oncogenic Ras are stimulated to grow by tumor promoters.68
Also, TGF beta does not inhibit proliferation of Ras transformed
cells.11, 12 During tumor progression, TGF beta causes different
cellular responses: from cytostatic and apoptotic to mitogenic and
invasive. 9–14, 69 In response to cancer cells, stroma secretes factors
that may in turn induce proliferation of resistant cells (Fig. 4),52, 70
Thus, cancer causing mutations are (i) molecular events that
are (ii) somatically heritable and (iii) selectable by conditions
that restrict cell proliferation/viability. In contrast, a number of
mutations, their exact nature (genetic, epigenetic or extra genetic),
extend of genetic instability may vary.
MOLECULAR THEORY: HALLMARKS AND POSTMARKS OF CANCER
Since the publication of outstanding millennium paper on
hallmarks of cancer,3 number 6 has become a magic number.
Six hallmarks include: (1) self sufficiency in growth signals, (2)
insensitivity to growth inhibitory signals, (3) evasion of apoptosis,
(4) limitless replicative potential, (5) sustained angiogenesis, and (6)
tissue invasion and metastasis.3 Number 6 is arbitrary because some
hallmarks can be combined together or subdivided. Rare cancers
may lack some hallmarks and, vice versa, hallmarks can be observed
without cancer. In this sense, hallmarks are not all equal. In particular,
second and third hallmarks (insensitivity to growth inhibitory
signals and evasion of apoptosis) are two faces of the fundamental
hallmark: namely, resistance to growth arrest and cell death (Fig. 5 B).
These involve inhibition of apoptosis and deregulation of cell
cycle. 4,8,20,27,71–77 This resistance is a manifestation of ‘oncogenic’
translation of ambivalent signaling (see Fig. 3) due to mutations
of oncogenes and tumor suppressors. In contrast, non oncogenic
resistance is due to prevention of cell damage (e.g., pumping out and
metabolizing of cytotoxic agents).61 All hallmarks of cancer can
be viewed as by products of oncogenic resistance (Fig. 5 B). For
example, same mutations (e.g., in Ras, p53, p16) that allow cells to
resist growth inhibition also cause cell immortality. As recently
discussed, a cell becomes immortal before it needs immortality.78
Therefore, immortality cannot be selected directly, because a cell
cannot tell the future. Cell immortality is a by product of resistance
to hypomitogenic growth arrest and hypermitogenic cell cycle
623
 Molecular Theory of Cancer

arrest.78 Thus, telomerase which is needed for immortality also

inhibits apoptosis.79 Noteworthy, that cancer cells still undergo drug
induced senescence.80–81
It has also been discussed that there is no specific mutations
for metastatic potentials.82–86 Perhaps there is direct selection for
resistance to growth arrest and cell death.78 Mutations are selected
only for an immediate advantage, not for the future ability of cancer
cells to metastasize to distant organs. The ability to metastasize is a
by product of the same mutations that render cells resistant to
growth arrest and apoptosis. In analogy, the fastest runners may also
be the farthest jumpers. The link between resistance and metastasis
has been suggested.87 However, it is crucial to distinguish between
non oncogenic (prevention of cellular damage) and oncogenic types
of resistance (ignoring the damage). Non oncogenic resistance
Figure 4. Selection for oncogenic resistance. In this example, TPA (tumor
may actually prevent carcinogenesis, because non oncogenic
promoter) inhibits proliferation of normal epithelial cells, selecting for
resistance substitutes for oncogenic.61 Similarly, the ability to induce resistant cells (R). Mutant Ras (or loss of CDK inhibitors) allows R-cells to
angiogenesis is a by product of mutations that produce oncogenic proliferate in the presence of TPA. The same oncogenic mutations (e.g.,
resistance (Ras, p53, HIF 1, autocrine mitogens).88–90 A cancer Ras) that render cells resistant to TPA allow cells to proliferate in response
cell that does not stimulate angiogenesis will benefit from a to TGF-beta, a physiological inhibitor of proliferation, which is secreted by
neighboring cancer cell that does it. Furthermore, even stromal cells stroma. Furthermore, TGF-beta can promote proliferation and invasion of
can substitute for cancer cells to produce VEGF.91 Therefore, such R-cells.
a direct selection for angiogenic activities would not occur, unless
the angiogenic activity is a manifestation of something else that is
beneficial to the cell itself. This is oncogenic resistance. Oncogenic A
resistance is the fundamental hallmark because other hallmarks are
its by products. Cancer is just a result of selection for resistance in
somatic cells.
Yet, there is an additional (rare) path to cancer, without selection
for resistance. This includes misplacement of embryonic and highly
proliferating cells such as trophoblasts. Interestingly, although
metastatic choriocarcinoma (originated by placental tropoblasts) is a
very aggressive cancer, it is very responsive to chemotherapy and is
curable.92,93 Similarly, testicular cancer and some childhood
leukemias and cancers are apoptosis prone and therefore curable
with chemotherapy.94,95 These are exceptional cancers, which arise
with a little prior selection for resistance.
Noteworthy, that not only testicular cancer but also
common cancers usually arise in apoptosis prone tissues
(hematopoietic bone marrow, lymphocytes, breast, prostate, colon
epithelial cells). Tumor progression is driven by selection for B
resistance to pro apoptotic stimuli. Therefore, cancer cells are more
resistant than parental normal cells. Yet, such cancer cells are not
necessarily more resistant than arterial smooth muscle cells (SMC) Figure 5. Hallmarks of cancer. (A) Traditional point of view. Accumulation
and dermal fibroblasts, for instance. Apoptosis reluctant cells of mutations leads to sequential acquiring of hallmarks of cancer. From
(e.g., SMC), do not need to acquire a hallmark such as apoptosis immortality that is often precedes transformation to metastatic potentials.
avoidance. Lack of selection perhaps prevents carcinogenesis. For (B) Hallmarks of cancer as a by-product of oncogenic resistance. Selection
example, monoclonal proliferation of mutant smooth muscle cells for resistance (apoptosis evasion and resistance to growth arrest) is a
is a basis of the atherosclerotic plaque,96 which is not cancer. This is driving force for accumulation of mutations. These mutations are manifested
as all hallmark of cancer. Depending on particular oncogenic mutations
consistent with the notion that suppression of apoptosis may
that confer oncogenic resistance, metastasis may appear early or late in
prevent carcinogenesis.97 tumor progression.
On the other hand, reactive proliferation and hyperplasia (with-
out any mutations) may have typical hallmarks of cancer such as Genetic instability: Genetic instability (high mutation rate) leading
invasion, metastasis and angiogenesis. After severe anemia, extra to aneuploidy, point mutations, gene deletion and silencing was
medullar hematopoiesis can take place in spleen (like metastasis). extensively discussed.98–101 Here I emphasize that genetic instability
Also, a reactive lymphocytosis imitates leukemia. Tumor like growth is an associated postmark of selection for resistance. Mutations that
occurs in development, wound healing (with neovascularization), render resistance, like any mutations, arise in unstable cells. If muta-
immune response and reactive hyperplasia. In all these conditions, tion is selected, then genetic instability is selected too.98 Genetic
there is selection for resistance. But without heritable mutations, instability provides a means for selection: mutation repertoire.98 The
resistant phenotype cannot be selected, not leading to cancer. driving force is cytotoxicity and growth inhibitory effects of carcinogens

624 Cancer Biology & Therapy 2005; Vol. 4 Issue 6

 Molecular Theory of Cancer
Figure 6. Benign tumor due to cooperation of two cell populations. Both cells
A and cells B behave as nontransformed cells in cell culture. When stimulated
by cell A, cell B behaves as transformed. Following cell division, the
daughter cell B moves apart from cell A, and behaves as normal (on the
tumor margin). Therefore, benign tumor does not invade. Malignant tumor
is shown for comparison.
and physiological inhibitors.61 In contrast, cancer cells that are cre-
ated by introduction of oncogenes are not genetically unstable.102
This confirms that genetic instability is a postmark of selection for
mutations rather than a by product of oncogenic transformation.
High mutation rate is a postmark of adverse conditions that cause
selection for resistance. In cytotoxic conditions, cells need mutations
to acquire resistance. For example, genetic instability emerges in
normal lymphocytes of children treated for leukemia.103 Also, cyto-
toxic carcinogens induce genetic instability.104 High mutation rates is
necessary for adaptive evolution of bacteria in adverse conditions.105,106
If one would like to claim universal laws that are common for
evolution of species and of somatic cells, then there might be
two laws. First, it is selection for resistance to adverse conditions that
drives evolution. In somatic cells, oncogenic resistance (resistance
due to mutations in oncogenes and tumor suppressors) to restrictive
factors is manifested as cancer. Second, genetic instability provides
a means (mutation repertoire) for selection for resistance.
Therefore, selection for resistance is associated with selection for
genetic instability.
MOLECULAR THEORY: FROM MOLECULES TO PATHWAYS TO CELLS
TO TISSUE TO ORGANISM
Molecular levels. For example, point mutations in p53 and Ras,
and methylation in the p16 promoter.3,4,8
Modular levels. These mutations (e.g., p53, p16, Ras, c myc)
alter signal transduction, allowing cells to proliferate in response to
signals that otherwise cause growth arrest and/or cell death (Fig. 3).
This is oncogenic translation of ambivalent signals.
Cellular levels. Due to ‘oncogenic translation of ambivalent
signaling’, cancer cells are resistant to growth arrest and apoptosis
(oncogenic resistance).61 The same mutations (e.g., Ras and mutant
p53) that allow cells to resist growth inhibition also cause immortality.78
www.landesbioscience.com Cancer Biology & Therapy
Tissue levels. First, alterations of the same oncogenes and tumor
suppressors that render cells resistant to growth arrest and apoptosis
(Ras, Akt, Raf, Bcl 2, loss of p53) also render cells capable to invade
and to induce angiogenesis. For example, oncogenic Ras can activate
secretion of VEGF and proteolytic enzymes that are needed
for angiogenesis and invasion surrounding tissues.88,107 Second,
mutations (including extra genetic alterations) can also occur in
stromal cells, which in turn can produce growth factors that activate
epithelial tumor cells. Like cooperating mutations result in fully
transformed phenotype, two altered cells can cooperate to grow a
tumor. For example, one cell may produce growth factor (e.g.,
PDGF) but not its receptor (Fig. 6). A neighboring cell may express
the receptor and thus will be phenotypically transformed, when the
first cell is around, precluding metastasis. Thus, from general
considerations, we can predict a tissue phenomenon that looks like
benign tumor (Fig. 6).
Benign tumors. Benign cell is elusive because it has no in vitro
counterpart. Unlike normal and malignant cells, which are well
defined in vitro, benign cell is not defined. In vitro, cells are either
normal, or immortal, or transformed. Immortalized cells do not
correspond to benign cells: by definition, immortalized cells do not
form tumors. Paradoxically, there is no benign cell (in vitro) but
there are benign tumors (in vivo). How can this be explained? For
example, mutant cells that produce GF can cooperate with cells that
express its receptor. Two cooperating cells (either one or both cells
with mutations), which depend on each other for transformed
phenotype, may form benign tumor. As shown in Figure 6,
cell B is not transformed. A complementing cell A causes
its phenotypical transformation. In contrast, malignant cell has
transformed phenotype on its own (Fig. 6). As an illustration,
growth factor confers a tumorigenic phenotype to human tumor
cells bearing its receptors but not to cells devoid of receptors.108
On an organism level, cancer is characterized by metastasis,
which (like angiogenesis, immortality and invasion) is a manifestation
of the same oncogenic mutations that cause oncogenic resistance to
growth arrest and apoptosis. Also, misplaced embryonic and
placental trophoblast cells may grow as tumors. Normal human
trophoblast cells share in vitro invasive properties of malignant
cells.109 Placental choriocarcinoma can metastasis to lung, brain,
liver of pregnant women.92 Noteworthy, that choriocarcinoma
are formed by placental cells, which belong to the baby not to the
mother. This leads us to the final level: cancer cells spreading
from one organism to another and living as unicellular
mammalian species.
Cancer cells as ‘species’. There are thousands of different cancer
cell lines, such as HeLa, which already live for 50 years in vitro.110
Can cancer cells live in a wild, like unicellular organisms?
Astonishingly, canine sarcoma spread from one dog to another as
venereal disease.111,112 Not sarcoma virus nor cellular DNA but
sarcoma cells themselves. Once sarcoma cells spread to a new dog,
the tumor grows progressively for about 4–6 months and then
regresses; lethal metastasis occurs in puppies and immunosuppressed
dogs.113 And the mutation in c myc promoter reveals that this
sarcoma cell ‘species’ has arisen in one dog decades ago and still live
in a wild.111,112 This free living cancer cell line is evolving as any
other unicellular pathogen, by acquiring the ability to escape
immune response. 114
625
 Molecular Theory of Cancer
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