2002 Nature Publishing Group

Accumulating evidence indicates that cellular function

and phenotype are highly influenced by heparan-
sulphate glycosaminoglycans (HSGAGs). HSGAGs are
members of the glycosaminoglycan family, which are
complex polysaccharides that are characterized by a
repeat disaccharide unit of uronic acid (either iduronic
or glucuronic acid) linked to a glucosamine (FIG. 1).
They arealso referred to asHS.
Present at the celltissueorgan interface, they have
been shown to have crucial regulatory roles in normal
physiological processes, such asembroyogenesis
1
, aswell
as in pathophysiological conditions, including the
processes of tumour onset and progression
2,3
. In vivo,
HSGAGsareusually found covalently attached to various
core proteins; these HSGAGprotein conjugates are
termed heparan-sulphate PROTEOGLYCANS (HSPGs).
Proteoglycansthat display HSGAG sidechainsareoneof
at least three types. The two main groupsof cell-surface
HSPGsincludetheSYNDECANSand theGLYPICANS. Together,
the syndecans and the glypicans provide an important
part of a cellssugar coat that isinvolved in cell signalling
at thecellextracellular matrix (ECM) interface.
The PERLECANS, conversely, are HSPGs that are
primarily secreted into the ECM. Importantly,
advancesin our understanding of HSGAG biosynthesis
including the discovery of many of the enzymesthat
are involved in the biosynthesis of HSGAGs, coupled
with the recent development of new molecular tools to
determine HSGAG structure have shown that poly-
saccharide structure and location can determine
whether HSGAG complex polysaccharides upregulate,
downregulate or have no effect on a given biological
process. The emerging view isthat by dynamically regu-
lating HSGAG structure at its cell surface and in the
ECM, a cell can respond to its microenvironment in
markedly different ways.
This review will focus on recent reports that have
revealed much about the role of HSGAGs in tumori-
genesis, tumour progression and tumour metastasis.
Importantly, we will focus on the roles that have been
elucidated for cell-surface HSPGs, as well as the roles
that have been postulated for the antitumour activity
of exogenously added highly sulphated HSGAGs
commonly referred to asHEPARINS.
HSGAGs
HSGAGs are present on the surface of every eukary-
otic cell, including both tumour cells and cells that
are important for tumour survival. These include the
endothelial-cell compartment that is proximate to a
growi ng tumour, where HSGAGs modulate the
process of angiogenesis. As befits their multifaceted
roles, HSGAGs on the tumour-cell surface have been
shown to be i mportant i n many aspects of tumour
ROLES OF HEPARAN-SULPHATE
GLYCOSAMINOGLYCANS IN CANCER
Ram Sasisekharan*

,Zachary Shriver*,Ganesh Venkataraman* and Uma Narayanasami

Cell-surface/extracellular-matrix heparan-sulphate glycosaminoglycans (HSGAGs) are complex

polysaccharides that are ubiquitous in nature, and that regulate several aspects of cancer
biology, including tumorigenesis, tumour progression and metastasis. Recently gained insights
into the structure of HSGAGs have extended our understanding of their role in the oncogenic
process. At present, clinical trials are examining the anticancer properties of exogenous highly
sulphated HSGAGs, including heparin and low-molecular-weight heparins, in addition to small
oligosaccharide heparin mimetics. Combined with our more intricate understanding of HSGAG
structure, this emerging structureactivity approach opens exciting avenues for the generation
of polysaccharide-based anticancer therapeutics.
PROTEOGLYCAN
A glycoprotein that consistsof a
coreprotein sequenceand
glycosaminoglycan extensions.
Proteoglycansthat contain
heparan-sulphate
glycosaminoglycan sidechains
arecalled heparan-sulphate
proteoglycans.
NATURE REVI EWS | CANCER VOLUME 2 | JULY 2002 | 5 2 1
*Biological Engineering
Division and

Center for
Biomedical Engineering,
MassachusettsInstituteof
Technology,Cambridge,
Massachusetts02139,USA.

Division of Hematology
and Oncology,New England
Medical Center,Tufts
University School of
Medicine,Boston,
Massachusetts02111,USA.
Correspondenceto R.S.
e-mail: rams@mit.edu
doi: 10.1038/nrc842
R E V I E WS
2002 Nature Publishing Group
5 2 2 | JULY 2002 | VOLUME 2 www.nature.com/reviews/cancer
R E V I E WS
have profound effects on tumour-cell growth kinet-
i cs and metastasi s formati on
3
. Speci fi cal ly, certai n
HSGAG sequences that are expressed on the
tumour-cel l surface seem to be pro-tumori geni c,
whereas others are anti -tumori geni c. By dynami -
cal l y regul ati ng the composi ti on and sequence of
HSGAGs, cancer cells modulate their growth kinet-
i cs and metastati c potenti al . HSGAGs on the
tumour-cell surface seem to mediate their effects by
regulati ng growth-factor si gnalli ng, cell adhesi on,
proli ferati on and mi grati on
3
. So, alterati ons i n the
l evel of expressi on of the protei n core, as wel l as
HSGAG structure and/ or densi t y on HSPGs, can
potenti al l y make cancer cel l s hi ghl y versati l e i n
modulating their behaviour.
But what have we recently learned about the roles
of HSGAGs i n tumour bi ology, and what i s the
potential for HSGAG-based anticancer therapeutics?
To answer these questi ons, we need to explore the
molecular structure of the oligosaccharide chains and
determi ne the changes i n HSGAG structure that
accompany alterations in the pathological status of a
cell, as well as differences between cell types.
HSGAG structure and function
HSGAGs are complex polysaccharides with enormous
structural diversity. Every HSGAG polysaccharide con-
tains a core backbone that consists of a disaccharide
repeat uni t of a glucosami ne li nked to ei ther an
iduronic or a glucuronic acid
4
(FIG. 1). The structural
complexity arises from the differential modification of
individual disaccharide unitswithin an oligosaccharide
chai n
5,6
. There are 48 possi ble di sacchari de uni ts,
which can form a complete HSGAG chain of 10100
disaccharide units. Modification can occur at the 2-O
position of uronic acid and the 6-O and 3-O positions
phenotype and development, i ncludi ng cellular
transformation, tumour growth, invasion and metas-
tasis. In vivostudies in mice indicate that changes in
the fi ne structure of tumour-cell-surface HSGAGs
SYNDECAN
A membrane-bound
proteoglycan that containsa
largeextracellular domain with
attached heparan-sulphate
glycosaminoglycan chains, a
conserved transmembrane
domain and asmall cytoplasmic
domain.
GLYPICAN
A heparan-sulphate
proteoglycan that istethered to
themembraneby a
glycosylphosphatidylinositol
anchor. Thecoreprotein
containsaconserved cysteine-
rich globular region and several
glycosaminoglycan attachment
sites.
PERLECAN
A proteoglycan that istypically
extruded into theextracellular
space.
HEPARIN
A highly sulphated member of
theheparan-sulphate
glycosaminoglycan family.
Typically present in mast cells,
whereit actsasastoragedepot
for proteases, heparin isused
pharmacologically asan
anticoagulant.
Summary
Heparan-sulphate glycosaminoglycans (HSGAGs) act at the cellextracellular-matrix (ECM) interface to modulate cell
signalling, thereby regulating howa cell perceives its environment.
HSGAGs interact with various extracellular signalling molecules: growth factors, morphogens, enzymes and
chemokines. The specificity of these interactions is dependent on HSGAG sequence, spacing of binding sites and the
three-dimensional structure of the HSGAG chain.
HSGAGs, depending on location and sequence, impinge on tumour onset and progression in various ways, some of
which are pro-tumorigenic and others of which are anti-tumorigenic.
HSGAGs at the tumour-cell surface actively modulate the tumorigenic process by regulating autocrine signalling loops
that lead to unregulated cell growth.
HSGAGs impinge on howan organism responds to a growing tumour, including the recruitment of cells of the
immune system to the tumour site, formation of a fibrin shell around the tumour that acts as a protective barrier and
development of newblood vessels to the site of the growing tumour.
Compelling clinical evidence indicates that pharmacological doses of heparin, a highly sulphated HSGAG, can have a
marked effect on tumour metastasis. Clinical trials have been designed to determine the exact benefits of heparin
therapy in cancer.
In addition, the low-molecular-weight heparins (LMWHs) a series of heparin fragments that share many of
heparins activities, including its anticoagulant effect, but lack several of its side effects might showeven greater
antitumour activity.
The advent of HSGAG sequencing technologies promises to usher in a newgeneration of LMWHs with potent
antitumour activity.
Growth
factor
Collagen
Cell-
surface
receptor Proteoglycan
HSGAG Disaccharide unit
O X
O H
O
NHY
O X
O
O X
CO O

O
O
O
ECM
Uronic acid
Glucosamine
Figure 1 | Structure and biology of heparan-sulphate glycosaminoglycans.Heparan-
sulphate glycosaminoglycans (HSGAGs; green lines) exist at the cell surface and also in the
extracellular matrix (ECM ), where theyare bound to proteins (red lines) to form proteoglycans.
Owing to the highlyhydrophilic nature of the HSGAG chains, proteoglycans have a Christmas-tree-
like extended conformation. The biosynthesis of HSGAGs leads to regions of aggregate chemical
character within the polysaccharide chain. The green squares indicate highlysulphated regions of
the polysaccharide chain, whereas the green circles indicate regions of undersulphation. Zooming in
further, all HSGAGs consist of a disaccharide unit of uronic acid (either iduronic acid or glucuronic
acid) that is attached to a glucosamine. Each disaccharide unit can be differentiallysulphated at the
2-O position of the uronic acid and/or the 6-O, 3-O positions of the glucosamine (designated in the
figure with a red X). In addition, the N-position of the glucosamine can be either sulphated,
acetylated or unsubstituted (designated with a red Y). All potential sites of modification are shown in
red. The diversityof chemical sequences that is contained within the polysaccharide chain enables
HSGAGs to bind to and modulate the activityof various growth factors (orange circles), chemokines
and enzymes at the cell surface and in the extracellular matrix (ECM ) (see TABLE1).
2002 Nature Publishing Group
NATURE REVI EWS | CANCER VOLUME 2 | JULY 2002 | 5 2 3
R E V I E WS
including FGF1, FGF2 and ANTITHROMBIN III (AT-III)
911
.
Longer oli gosacchari de sequences can bri dge pro-
tei nprotei n complexes, acti ng as a platform for
homo-oligomerization and/or bridging a ligand to its
receptor. In this case, specificity arises from the spac-
i ng of the tetra-to-hex-asacchari de bi ndi ng si tes
along a polymer chain. Such interactions have proven
to be important for several ligandreceptor systems
12
,
including binding of FGF2 to the various isoforms of
the FGF receptor
13
. So, a given HSGAG chain that is
present on a proteoglycan in vivocan be considered
to be a seri es of i nterconnected bi ndi ng si tes for a
host of signalling molecules the exact sequence of
which is under dynamic control by the cell (FIG. 1). In
addition to the information content that is inherent
i n the pri mary sequence of the HSGAG polymer, a
final level of binding specificity is determined by the
conformati onal flexi bi li ty of the polysacchari de
backbone speci fi cally by the i duroni c aci ds that
are contained within it (BOX 2).
These specific interactions allow HSGAGs to fine-
tune protein function and regulate diverse biological
processes. By dynamically regulating its cell-surface
coat, a cell can alter i ts phenotype. For example,
changes in HSGAG structure act as a developmental
swi tch between FGF1 and FGF2 si gnalli ng i n neu-
roepi theli um
14
, and producti on of an extracellular
sulphatase i nduced by the morphogen Soni c
hedgehog, which acts on the nascent HSGAG chain
regulates HSGAG-dependent WNT signalling in
the developi ng embryo
15
. Also, speci fi c HSGAG
sequences that are present at the cell surface promote
formation of active FGF oligomers, coupling them to
thei r cell-surface receptor, whereas other HSGAG
sequences i n the ECM lock FGF i nto an i nacti ve
stored form
13
.
By identifying HSGAG sequences that bind with
high affinity to proteins, understanding on a molecu-
lar basis how these HSGAGs bind, and determining
the bi ologi cal i mpact (such as whether speci fi c
HSGAG sequences promote or i nhi bi t activi ty), a
framework can be developed for understanding the
role of HGSGAG complex polysaccharides in biologi-
cal systems, including in cancer in humans. In addi-
tion, such an understanding will provide the basis of
next-generation, novel therapeutics to control a wide
vari ety of di sease processes, the most i mportant of
which iscancer progression and metastasis.
HSGAGs in cancer
Wi th respect to cancer onset and progressi on, the
structural complexity of tumour-cell HSGAGs (both
at the cell surface and extruded i nto the ECM)
enables them to modulate directly several aspects of
tumour-cell phenotype, including growth kinetics,
invasiveness and metastatic potential
3,18
(FIG. 2). So, a
given tumour-derived HSGAG or HSPG can be pro-
tumori geni c or anti -tumori geni c dependi ng on
whether it is anchored at the cell surface or present in
the ECM as soluble-free GAGs
19
, as well as depending
on the HSGAG sequence.
of glucosamine
2
. Additionally, the N-position can be
sulphated, acetylated or unmodified. All of these possi-
ble combinations result in great structural diversity. It
i s only recently that the molecular tools have been
developed to study HSGAG structure and to identify
key structurefunction relationships (BOX 1). A short-
hand has been developed to identify HSGAG oligosac-
charides; this nomenclature is used to define HSGAG
structure and isoutlined in BOX 1.
One of the consequences of the immense structural
diversity of HSGAGs is that these molecules are able to
bind and interact with a widevariety of proteins, such as
growth factors, chemokines, morphogensand enzymes
(TABLE 1). Among other signalling molecules, these
include growth factors that are important for tumour
development, such as fibroblast growth factors (FGF1
and FGF2), vascular endothelial growth factor (VEGF),
hepatocyte growth factor, transforming growth factor-
, and platelet-derived growth factor
7
. As shown in
TABLE1, these HSGAGprotein interactions are numer-
ous and are crucial for the signalling molecule or
enzymeto beableto exert itsproper biological function.
Predomi nantly, extracellular protei ns bi nd to a
tetra- or hexasacchari de
8
moti f wi thi n an HSGAG
oligosaccharide chain, as observed by crystal-structure
analysi s of several protei nHSGAG complexes,
PROPERTY-ENCODED
NOMENCLATURE
(PEN). A rational system for
defining apolymer that isbased
on thepropertiesof its
monomeric units. Thissystem
formsthebasisfor a
computationally aided
sequencing approach for
heparan-sulphate
glycosaminoglycan complex
oligosaccharides.
ANTITHROMBIN III
(AT-III). An inhibitor of the
coagulation cascade, specifically
Factor Xaand Factor IIa
(thrombin). Binding of AT-III to
aspecific pentasaccharide
sequencein heparan sulphate
resultsin aconformational
changein AT-III, increasing its
anticoagulant activity by orders
of magnitude. Factor Xaisa
serineproteaseof the
coagulation cascade. Factor Xa
activatesthrombin the
penultimatestep of the
coagulation cascade.
Box 1 | Sequencing complex polysaccharides
One of the main barriers to studying heparan-sulphate glycosaminoglycan (HSGAG)
function had been the inability to sequence these molecules. As with DNA and proteins,
complex polysaccharides contain sequence information. For complex polysaccharides,
this sequence is typically read from the non-reducing end to the reducing end. For
example, a tetrasaccharide that consists of two iduronic acid residues both 2-O
sulphated and two glucosamine residues, both with N-sulphation and the non-reducing
glucosamine that contains an additional sulphate at the 6-O position would be
abbreviated as I
2S
H
NS,6S
I
2S
H
NS
.
The delay in the development of sequencing technology was due to several factors.
One reason is that there have been very fewtools, such as enzymes and chemical
methods, to cleave HSGAGs precisely. Also, unlike other biopolymers, including DNA
and proteins, there is no in vitrosystem for amplifying sequences of interest. Finally,
purification of the highly anionic HSGAG sequences is a great challenge. As such, only
in the past three years have effective sequencing procedures been put in place. These
techniques integrate end-labelling (or metabolic labelling) of the unknown
oligosaccharide, which allows for enzymatic or chemical cleavage, separation and
identification of the products by means of high-performance liquid chromatography,
gel electrophoresis or capillary electrophoresis. In this vein, three distinct, but related,
procedures have been developed
4850
. Each of these closely approximates the
MaximGilbert strategy for sequencing DNA, as HSGAG sequences are read from the
non-reducing end to the reducing end.
Recently, a newapproach has been developed that, in many ways, parallels advances
that have been made in other areas of bioinformatics. This procedure, called PROPERTY-
ENCODED NOMENCLATUREmatrix-assisted laser-desorption mass spectrometry (PEN-
MALDI), which couples mass spectrometry with a bioinformatics computational
framework, has been used to sequence HSGAG sequences that are involved in anti-
coagulant function and growth-factor binding
51
. In addition, this technique has been
used to sequence mixtures of HSGAG oligosaccharides, and has been successfully
coupled to a chip-based separation procedure
52
.
Similar advances in sequencing, isolation and characterization procedures promise to
improve our understanding of the roles of specific HSGAG sequences in various
biological processes, including cancer pathogenesis.
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R E V I E WS
The association between specific mutations in
HSGAG-related genes and inherited syndromes that
increase cancer risk implicates these molecules in
tumorigenesis
25
. SimpsonGolabiBehmel syndrome
(SGBS) is a complex congenital overgrowth syndrome
with features that include MACROGLOSSIA, MACROSOMIA, and
renal and skeletal abnormalities, as well as an increased
risk of certain malignancies. Most casesof SGBSseem to
arise as a result of either deletions or point mutations
within the gene that encodes glypican-3 (GPC3) at
Xq26. GPC3expression isalso downregulated in a num-
ber of cancers, including breast and ovarian carcinomas,
and mesotheliomas.
In addition to their role in initial cell transforma-
tion, tumour-cell-surface HSGAGs bind growth fac-
tors, cytoki nes and structural protei ns that are
involved in modulating autocrine and paracrine sig-
nalling loops that are important for tumour growth
and progressi on
26
. As wi th other processes that are
described in this review, the diverse structural charac-
teri sti cs of HSGAGs allow them to act ei ther as
i nhi bi tors or potenti ators of these si gnalli ng loops,
depending on the sequence context
3
. Recent studies
have shown that, in vitro, tumour-cell-surface
HSGAGs can promote growth-factor signalling and
tumour-cell proli ferati on (FI G. 2). For example,
HSGAG sequences of at least a decasacchari de i n
length, contai ni ng an I
2S
H
NS,6X
I
2S
moti f (X = ei ther
sulphated or unsulphated)
27
are beli eved to bi nd
Recent evi dence hi ghli ghts the fact that cancer
cells, as part of the transformation process, alter their
cell-surface HSGAG profi le, i ncludi ng di fferenti al
expressi on of parti cular proteoglycan protei n-core
sequences, as well as altering the HSGAG fine struc-
ture of a given proteoglycan
20
. HSGAGs are involved
in the initial oncogenic transformation of a normal
cell to a tumour cell
21,22
. Changes in both the expres-
sion level and the oligosaccharide sequence charac-
teri sti cs of cell-surface HSPGs have been shown to
correlate wi th transformati on i n several mali gnan-
cies. For example, syndecan a HSGAG proteogly-
can i s requi red to mai ntai n the di fferenti ated
morphology and locali zati on of epi theli al cells.
Syndecan-1expression is downregulated in various
malignant tumours, including uterine carcinomaand
multiple myeloma. Its expression decreases as in situ
carci noma progresses to i nvasi ve carci noma
23
.
Specific HSGAG structural changes have been noted
duri ng mali gnant transformati on of colon cancer
cells from adenoma to carcinoma
24
. In a similar man-
ner, glypi can-1, another cell-surface HSPG that
closely regulates cell growth and divi si on, has been
shown to act as a negative regulator of cell prolifera-
tion for certain tumour types
22
. Glypicans have also
been found to modi fy cellular responses to bone
morphogeneti c protei ns and i nsuli n-li ke growth
factor-2 factors that are i mportant i n cellular
division and differentiation.
MACROGLOSSIA
Tongue enlargement, leading to
functional and cosmetic
problems.
MACROSOMIA
Atypically largebody size.
Table 1 | Partial list of proteins that bind to HSGAGs and their biological effects
Area Factor Result Proposed effect on cancer
Coagulation Antithrombin III Conformational change
9
Inhibition of fibrin shell crucial
for tumour-cell survival
Thrombin Ternarycomplex formation
53
M odulates coagulation system
Tissue-factor pathway Release into the circulation
54
M odulates coagulation system
inhibitor
Growth factors/ Fibroblast growth factor Receptor specificity, In the extracellular matrix,
morphogens oligomerization
55
HSGAGs sequester growth
factors, forming a storage
depot. O n the cell surface,
theybind growth factors,
activating an autocrine-cell
signalling loop
Hepatocyte growth factor Growth-factor sequestering
56
Promotes tumour growth
WNT Gradient formation
15,57,58
K eyrole in the diffusion of
morphogens; regulation of
differentiation
Angiogenic factors Endostatin Low-affinityreceptor; cell specificity
31
Blocks angiogenesis
VEGF Signalling
28
Induces angiogenesis
Cytokines/ Interleukins (for example, Activates growth-factor M odulates host immune-cell
chemokines IL-8) sequestering
40
response to tumour cells
M IP-1 Chemokine gradient formation
41
Cellcell P-selectin M odulate leukocyte homing
59
, K eymechanism bywhich
interactions tumourplatelet interactions sulphated GAGs promote
metastasis
Cellmatrix Laminin Adhesion to ECM
60,61
Contact inhibition of tumour
interactions Fibronectin Focal-adhesion formation
62
growth and dedifferentiation
Enzymes Heparanase Substrate
34,35
, ECM Provides a barrier to
degradation metastasis; sequesters
factors involved in promoting
cancer-cell invasion
ECM , extracellular matrix; GAGs, glucosaminoglycans; HSGAGs, heparan-sulphate glucosaminoglycans. M IP-1, macrophage
inflammatoryprotein-1; VEGF, vascular endothelial growth factor.
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NATURE REVI EWS | CANCER VOLUME 2 | JULY 2002 | 5 2 5
R E V I E WS
modulate their HSGAG cell-surface profile to become
ei ther more or less sensi tive to angi ogeni c si gnals
from a growing tumour (FIG. 2).
Metastasis. By mediating interactions between cancer
cells and platelets, endotheli al cells and host organ
cells, HSGAGs regulate tumour metastasi s to si tes
such as the liver, lungs or spleen
18,32
. Several in vitro
and in vivoexperiments in human cancer cells have
shown that HSGAGs add another level of complexity
to tumour-cell behaviour beyond that conferred
by genetic defects and aberrant protein expression
by participating in the cellcell and cellECM adhe-
sion processes that are required for tumour metasta-
si s
18
(FI G. 2). For example, HSGAG proteoglycan
sequences that have been i solated from li ver si nu-
soidal blood-vessel cells have been shown to promote
the selective metastasis of mouse tumours to the liver
in effect, acting as a molecular beacon for tumour
cells in circulation
33
.
In addition to their role in mediating tumour metas-
tasis, HSGAGs in the ECM, along with structural pro-
teins such as collagen and laminin, make up a physical
barrier to tumour metastasis. But during invasion and
metastasis, tumour cells secrete enzymes that degrade
both the protein (e.g. matrix metalloproteinases) and
polysaccharide (e.g. heparanases) components of the
basement-membrane barrier. Recent studies have
revealed a direct correlation between the production of
heparanasesand the invasiveness of tumour cells
17,34,35
.
Heparanase expression by several human tumour types,
including colorectal and pancreatic carcinomas, has
been shown to increase during a tumours transition,
from benign to malignant and onto invasive carcinoma.
In addition, transfection of the gene that encodes
heparanase into a non-metastatic cell type results in a
marked phenotypic change and greatly enhanced
specifically to FGF2 and its transmembrane receptor,
promoting the formation of a signalling complex at
the cell surface. Tumour cells have been reported to
acti vely i nfluence the affi ni ty of thei r HSPGs for
FGF2, as well as for other growth factors, by modu-
lati ng the overall densi ty and SULPHATI ON PATTERN of
their HSPGs.
Indirect effects of HSGAGs on tumour growth
Angiogenesis. In addition to the role of tumour-cell-
surface HSGAGs in directly modulating cancer-cell
proliferation and progression, HSGAGs that are pre-
sent on the surface of endothelial cells have an indirect
effect on tumour growth. For example, HSGAGs are
able to modulate angi ogenesi s, whi ch i s cruci al for
tumour growth beyond a size of 12 mm diameter
28,29
.
HSGAGs can either inhibit or promote neovascular-
ization by regulating signalling by the cellular FGF2
(REF. 30) or VEGF
28
receptors. This highlights an impor-
tant concept i n the HSGAG fi eld: on the one hand,
HSGAGs on the tumour-cell surface modulate FGF2-
facilitated autocrine signalling loops that promote cell
proliferation, whereas, on the other hand, HSGAGs on
the endothelial-cell surface mediate FGF2 signalling to
i nduce angi ogenesi s. HSPGs i n the ECM modulate
both of these processes by binding to and sequestering
signalling moleculessuch asFGF2.
To make the situation more complex, it has been
shown recently that HSGAGs on endothelial-cell sur-
faces can serve as a bi ndi ng si te for the potent anti-
angi ogeni c factor endostati n. In thi s case, speci fi c
sequences on glypicans are required for the specificity
of endostati n bi ndi ng, as well as i ts pronounced
effects on endothelial cells
31
. Several studies have indi-
cated that the HSGAG binding site for endostatin is
distinct from that of pro-angiogenic factors, such as
FGF. This raises the possibility that endothelial cells
SULPHATION PATTERN
Each HSGAG disaccharideunit
can bedifferentially sulphated at
four possiblepositions. On the
uronic acid, the2-O position
might besulphated or
unsulphated. For the
glucosamine, the6-O and
3-O positionsmight also be
sulphated or unsulphated.
Finally, theN-position of the
glucosaminecan be
N-sulphated, acetylated or
unsubstituted.
Box 2 | Specificity of HSGAG binding to proteins
Protein binding specificity arises from conformational
considerations of the linear heparan-sulphate
glycosaminoglycan (HSGAG) sequence. Shown is a schematic
of an HSGAG hexasaccharide, with the structure of
U
2S
H
NS,6S
I
2S
H
NS,6S
I
2S
H
NS,6S
(red) bound to fibroblast growth
factor-2 (FGF2). FGF2 binding to the hexasaccharide induces
a kink in the helical oligosaccharide chain from the second to
the fourth monosaccharide residues (H
NS,6S
I
2S
H
NS,6S
), enabling
high-affinity (and highly specific) binding to occur. The
specific iduronic-acid conformation within a binding
sequence will dictate whether the oligosaccharide sequence
can be accommodated by the proteins binding site.
Furthermore, sampling of the conformational space enables
optimal topological positioning between substituents on the
protein and the oligosaccharide namely, the sulphate
moieties of the saccharide and the basic residues of the
protein. In this manner, an analogy can be drawn between
protein binding to HSGAGs and protein binding to DNA. In
both cases, protein binding induces a conformational change
in the helical chain of the acidic, polyanionic biopolymer, and
the specificity of this kink leads to high-affinity binding.
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R E V I E WS
this, researchers have examined other possible effects of
UFH and LMWH on tumour progression and metasta-
sis. These studies have indicated that heparin might
interfere with tumour progression and metastasis by
meansof several mechanisms
3,32,3438
(FIG. 2).
Heparins highly sulphated HSGAGs are
potent anticoagulants that have been used for over 60
years to treat and prevent thromboembolic disorders.
These include deep-vein thrombosis, pulmonary
embolism, arterial thromboses, and acute coronary
syndromes such as myocardial infarction and unstable
angina. The use of UFH and LMWHs to treat venous
thrombosis in cancer patients has led to the observa-
tions in large clinical trials that this treatment also
prolongs cancer patient survival
16,36,37,39
. Several other
anecdotal clinical observations of antitumour activity
of heparins have been reported over the past four
decades. These clinical findingshave been substantiated
in various animal models, showing that heparin
inhibits tumour invasion and metastasis
32
. Prospective
controlled clinical trials that involve LMWHs in cancer
patients are underway to investigate further the effects
of heparin or LMWHsin cancer patients. But how does
heparin elicit thisantitumour effect?
Anticoagulation. Hepari n i nterferes wi th the for-
mation of the fibrin coat that surrounds the tumour
cells. In fact, the coagulation and fibrinolytic systems
are closely i nvolved i n both tumour growth and
metastasis. Cancer patients usually experience several
haemostatic abnormalities, including elevated levels
of fibrinogen, increased platelet counts and chronic
activati on of a coagulati on system cal led di ssemi -
nated intravascular coagulation. Cancer treatments
such as chemotherapy, surgery and placement of
intravenous catheters enhance this pro-thrombotic
state. The in vivoi nteracti ons between cancer cells,
endotheli al cells and platelets are medi ated by pro-
coagulants such as tissue-factor and urokinase-type
plasminogen-activator receptors
16,36
.
Tumour cells express high levels of these procoagu-
lants, leading to THROMBIN production and the formation
of a fibrin shell around the tumour (FIG. 2). This shell is
thought to shield the tumour from the host immune
response and confer resistance to chemotherapy. It also
indirectly promotes tumour-cell proliferation, invasion
and metastasis, because fibrin interacts with proteins in
the ECM, basement membranes, and adhesion mole-
cules on endothelial cells and platelets. The anticoagu-
lant activity of heparin can interfere with pro-coagulant
and pro-fibrinolytic processes, preventing the formation
of thefibrin shell
36,37
.
Immunemodulation. Heparin has also been proposed
to inhibit metastasis by making circulating cancer cells
more vulnerable to the immune response. In addition to
preventing the formation of the protective fibrin shell
and thereby providing natural killer cells with easier
access to tumours, heparin can also bind and regulate
the activities of several cytokines. Heparin binds to the
granulocyte and macrophage chemotactic factor C5a, as
metastatic potential. Heparanaseshave also been shown
to promote tumour growth by releasing growth factors
that are normally sequestered by HSGAG proteoglycans
in theECM.
Antitumour effects of heparins
Initially, it was thought that the antitumour effects of
unfractionated heparin (UFH) and LOW-MOLECULAR-
WEIGHT HEPARINS (LMWHs) were intimately linked to
their anticoagulant effect, as cancer patients often pos-
sess an activated coagulation system and are at an
increased risk for thromboembolism. However, other
anticoagulants, including vitamin-K antagonistssuch as
warfarin, do not have similar antitumour effects. Given
LOW-MOLECULAR-WEIGHT
HEPARIN
(LMWH). Developed to
maintain thepotent
anticoagulant affect of heparin
but to reducethenumber of side
effects. LMWHsaregenerated
by enzymatic or chemical
means.
THROMBIN
Also known asFactor IIa, it isthe
penultimatefactor of the
coagulation cascade. Thrombin
convertsfibrinogen into fibrin,
which isultimately responsible
for clot formation.
NK cells
d Growth
factor
Platelet
P
I
Thrombin
activation
e Signalling,
proliferation
a
b Heparanase
Heparin
d
c
Endothelium
Formation
of fibrin
coat around
tumour cell
M etastasis
Figure 2 | Role of heparan-sulphate glycosaminoglycans
in tumour metastasis.Heparan-sulphate
glycosaminoglycans (HSGAGs; green lines) function at the
tumour-cell surface to mediate metastasis. a | Cancer-cell-
surface HSGAGs can act as ligands for P-selectin (P), which
mediates adhesion either to platelets or to the endothelial lining
of the capillarysystem. This allows cancer cells both to
extravasate and enter the bloodstream, as well as to
metastasize to other organs. Addition of exogenous heparin
competes with P-selectin binding, inhibiting tumour-cell
adhesion processes. b| Heparanase cleaves HSGAGs,
releasing growth-promoting factors and promoting tumour
metastasis. Pharmacological doses of heparin are thought to
inhibit heparanase action. c | Cell-surface HSGAGs also act as
coreceptors for integrins (I), mediating cancer-cell adhesion to
blood vessels to promote extravasion. Pharmacological doses
of heparin are also believed to interfere with these processes by
competing with cancer-cell-surface HSGAG binding to
integrins. d| Cancer-cell-surface HSGAGs also contain
sequences that modulate local coagulation, specificallyby
modulating the activityof coagulation serine proteases such as
thrombin (Factor IIa). Tumour procoagulants promote the
formation of a protective layer of fibrin around the tumour, and
are also inhibited byheparin. This coat prevents attack by
natural killer (NK ) cells of the immune system. e | Finally,
HSGAGs at the tumour-cell surface interact with growth factors
(circles), such as fibroblast growth factor and vascular
endothelial growth factor, to regulate the proliferation and
migration of cancer cells through autocrine signalling loops.
2002 Nature Publishing Group
NATURE REVI EWS | CANCER VOLUME 2 | JULY 2002 | 5 2 7
R E V I E WS
activi ty of the polysacchari de chai n, rather than to
increase their antitumour activity these might not
be optimal agents to inhibit tumour growth and/or
metastasi s. Further analysi s of LMWHs or hepari n
mimetics
44,45
will also increase our understanding of
the role of heparin in the metastatic process.
Future directions
From a broad perspective, HSGAGsseem to serve mul-
tifaceted functions in tumour biology. Some of these
roles are outlined here; undoubtedly, others will come
to light as we learn more about the structure and func-
tion of HSGAG complex polysaccharides. We are only
beginning to understand that HSGAG structures are
not static and that cells dynamically regulate their
HSGAG sugar coat to modulate intracellular signalling
pathwaysin highly specific ways.
New technologies that have been developed to
analyse and synthesize complex polysaccharides are
unravelling the importance of glycobiology in cancer
pathogenesis. Gaining better insight into the
structurefunction relationshipsof complex polysaccha-
rides is key to understanding how these molecules
regulate different aspectsof cancer biology and to devel-
oping targeted therapeutics.Glycoprofiling cancer cells
by mapping cell-surface HSGAGs might provide an
opportunity to develop important prognostic toolsand
diagnostic screens for cancer detection and staging.
Using the GAG profile of a tumour, we might be able to
predict its growth or metastatic potential, as well as its
potential response to therapy. Recent advances in the
knowledge of HSGAG chemistry and biology might
eventually make it possible to create LMWHsthat target
specific attributesof varioustumoursand develop other
HSGAG-based interventions
46,47
. Thiswill open thedoor
to developing polysaccharide-based cancer therapeutics.
well asto interleukin-8(REF. 40) and macrophage inflam-
matory protein-1 (REF. 41). This promotes leukocyte
homing and immunedestruction of tumours.
Cell adhesion. In mi ce, pharmacologi cal doses of
heparin have been found to block tumour-cell adhe-
sion specifically by interfering with the function of
the platelet cell-surface adhesion protein P-selectin
18,53
.
Heparin has been proposed to inhibit tumour metas-
tasis by blocking the P-selectin-mediated interaction
between platelets and the si alylated, fucosylated
mucins that reside on the surface of circulating carci-
noma cells. Adhesion to platelets is an important step
in metastasis formation. Adhesion to endothelial cells
and ECM proteinsmight also be affected by heparins.
Inhibition of heparanase. In addition to the potential
roles for heparin in modulating immune function, cell
adhesi on and coagulati on, some forms of hepari n
have also been shown to inhibit heparanase activity.
This prevents the heparanase-mediated breakdown of
the polysacchari de barri er to metastasi s, and also
inhibits the release of pro-angiogenic factors such as
FGF2 (REF. 42). Hepari n mi meti cs that i nhi bi t
heparanase activity have shown preliminary efficacy
in rodent cancer models
43,44
.
Heparin is a multifaceted drug that binds to several
factors and therefore impinges on various biological
processes. It is unclear which mechanism, or combi-
nati on of mechani sms, actually medi ates the
in vivoantitumour effects of heparin. With the devel-
opment of new molecular tools to analyse hepari n
structure and function, it should be possible to design
new, second-generation LMWHs with more defined
activities. It is important to note that existing LMWHs
have been developed to maximize the anticoagulant
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Acknowledgements
The authorswould like to acknowledge financial assistance from
the Burroughs Wellcome Foundation, the Arnold and M abel
Beckman Foundation, the CapCure Foundation and the National
Institutesof Health.
Online links
DATABASES
The following terms in this article are linked online to:
C a n c e r. g o v: http://www.cancer.gov/cancer_information/
breast cancer | colon cancer | colorectal cancer | mesotheliomas|
multiple myeloma | ovarian cancer | pancreatic cancer | uterine
carcinoma
L o c u sL in k : http://www.ncbi.nlm.nih.gov/LocusLink/
bone morphogenetic proteins| collagen | endostatin | FGF1 | FGF2 |
glypican-1 | GPC3| heparanases| hepatocyte growth factor |
insulin-like growth factor-2 | interleukin-8 | laminin | platelet-derived
growth factor | P-selectin | Sonic hedgehog | syndecan-1 |
transforming growth factor- | VEGF | WNT
O M I M : http://www.ncbi.nlm.nih.gov/Omim/
SimpsonGolabiBehmel syndrome
FURTHER INFORMATION
C o n so rtiu m fo r F u n c tio n a l G lyc o m ic s:
http://glycomics.scripps.edu
G lyc o fo ru m h o m e p a g e : http://www.glycoforum.gr.jp
Access to this interactive links box is free online.