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Anti-Metastatic Activities of Heparins

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Heparins are commonly administered to cancer patients for the treatment and prophylaxis of thromboembolic events. Importantly, apart from the anti-thrombotic action of these drugs, several clinical trials have demonstrated an improved survival of cancer patients who were administered low-molecular-weight heparins (LMWHs). This improved survival was independent of the anti-thrombotic efficacy, since vitamin K antagonists did not improve clinical prognosis. Moreover, this protective effect was not the result of an inhibition of the growth of primary tumors, but rather the prevention of the spreading of cancer through metastases. This has been also shown in some animal experiments.
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Review Article
 
Anti-Metastatic Activities of Heparins

Marian Simka1 and Tomasz Urbanek

Department of Angiology, SANA Institute, Pszczyna, Poland [M. Simka]; Department of General and Vascular
Surgery, Silesian Medical University, Katowice, Poland [T. Urbanek]

Heparins are commonly administered to cancer patients for the treatment and pro-
phylaxis of thromboembolic events. Importantly, apart from the anti-thrombotic
action of these drugs, several clinical trials have demonstrated an improved survival
of cancer patients who were administered low-molecular-weight heparins (LMWHs).


This improved survival was independent of the anti-thrombotic efficacy, since vita-

min K antagonists did not improve clinical prognosis. Moreover, this protective

effect was not the result of an inhibition of the growth of primary tumors, but rather

the prevention of the spreading of cancer through metastases. This has been also

shown in some animal experiments. The protective effect of heparins, however,
could be seen only for some kinds of cancer. This review presents the most likely

Keywords:
mechanisms by which heparins and heparin derivatives attenuate cancer metasta-

ses. Most likely, heparin-dependent inhibition of metastases could be secondary to
heparin
a restraint of P- and L-selectin-mediated interactions of platelets with circulating

neoplastic cells, a modulation of the chemokine CXCL12/CXCR4 axis, an inhibition of
selectin

heparanase activity, or the inhibition of angiogenesis in the tumor. The combined
CXCL12
effect of the above-described mechanisms should be also taken into account. This

potential anti-metastatic role of heparins may imply that cancer patients should be
CXCR4
administered LMWHs instead of oral anticoagulants for the prevention and treatment

of thromboembolic events. Clinical recommendations on LMWHs in cancer patients
heparanase
should be revisited in regards to the anti-metastatic efficacy of these drugs. Addi-

metastasis
tionally, findings regarding heparins may provide a useful framework for research on
novel anti-metastatic drugs.

Journal of Cancer Molecules 5(1): 3-8, 2009.


Introduction

There is also strong evidence for the efficacy of low-dose

unfractionated heparins, as well as for LMWHs, in the
In the last decade, several molecular-targeted anticancer
reduction of venous thromboembolism following surgery in
drugs became available, primarily for clinical trials, but also
these patients [5,6]. Yet, in comparison with other surgical
for general clinical practice. These included monoclonal
patients, it is recommended to use higher prophylactic
antibodies and particles targeting growth factors and
doses of LMWHs [5,8]. Moreover, hospitalized and bed-
cytokine receptors. No obvious clinical advantage, how-
ridden cancer patients who are managed conservatively
ever, was observed with those agents, even if small subsets
should also receive adequate heparin thromboembolic
of patients benefited from such therapies. Nevertheless,
prophylaxis [9,10].  
such new treatments represented a novel strategy in the
Notably, in addition to the anti-thrombotic action of these
fight against cancer, as they have focused mainly on tumor-
drugs (even if some authors have found this issue contro-
host tissues interactions, and not on eliminating the cancer
versial [11-13]), results of several clinical trials have demon-
cells, which still seems to be an extremely difficult task. In
strated that LMWHs improve the survival of cancer patients
this context, administration of heparins or heparin deriva-
[14-18]. For example, in the FAMOUS (Fragmin Advanced
tives could be a promising therapy because it is not directed
Malignancy Outcome Study) study, prophylactic doses of
at killing cancerous cells, but at modulating the crosstalk
dalteparin, a LMWH, were compared with placebo for
between neoplastic cells and host tissues.
primary thromboembolic prophylaxis in cancer patients. In
Heparins, low-molecular-weight heparins (LMWHs2, Table
the subgroup of patients with good clinical prognosis,
1) in particular, are commonly administered to cancer
administration of LMWH significantly improved their survival
patients for the treatment and prophylaxis of thromboem-
[17]. In the MALT (Malignancy and Low Molecular Weight
bolic events [1,2]. According to the current knowledge,
Heparin) study, 6 weeks of administration of another LMWH,
there exists many links between the coagulation cascade
nadroparin, resulted in an improved survival in advanced
and cancer [3,4]. Cancer patients undergoing surgery have
cancer patients with a life expectancy over 6 months [18].
at least a doubled risk of perioperative deep venous throm-
Similar findings have been also reported from the CLOT
bosis in comparison with non-cancer subjects [5,6], and the
(Comparison of Low-Molecular-Weight Heparin vs. Oral
occurrence of thromboembolic complications is a significant
Anticoagulant Therapy for the Prevention of Recurrent
predictor of decreased survival in oncologic patients [7].
Venous Thromboembolism in Patients with Cancer) study,

which assessed the efficacy of secondary (i.e., after previ-
Received 12/21/08; Revised 3/19/09; Accepted 3/19/09.
1

ous thrombosis) prophylaxis in cancer patients with good
Correspondence: Dr. Marian Simka, Department of Angiology, SANA
Institute, ul. Wodzislawska 78, 43-200 Pszczyna, Poland. Phone/Fax:
clinical prognosis [16]. However, such an anti-cancer
+48-322120498. E-mail: mariansimka@poczta.onet.pl
protective effect was not found in the other clinical trial
2Abbreviations: LMWH, low-molecular-weight heparin; VEGF,
assessing the survival benefit in patients with advanced
vascular endothelial growth factor.
cancer [19](Table 2).
© 2009 MedUnion Press http://www.mupnet.com                                                                                                                    3 
 

Simka & Urbanek. J Cancer Mol 5(1): 3-8, 2009
Table 1: Chemical characteristics of unfractionated heparins and LMWHs

Heparin
Mode of production
Molecular mass
Structure at the non-
Structure at the
reducing end
reducing end
Unfractionated heparins

About 20000 Da in


(heparins are a heterogeneous
average
mixture of straight-chain
anionic mucopolysaccharides
derived mainly from porcine
intestine; bovine lung is the
alternative source of heparin)
Enoxaparin
Alkaline beta-eliminative
3500-5500 Da with a
4-enopyranose uronate
2-N,6-O-disulfo-D-
(a sodium salt of LMWH)
cleavage of the benzyl
characteristic value of
glucosamine
ester of heparin
about 4500 Da
Dalteparin
Nitrous acid depolymeri-
5600-6400 Da with a
2-O-sulpho-alpha-L-
6-O-sulpho-2,5-
(a sodium salt of LMWH)
zation of heparin
characteristic value of
idopyrano-suronic acid
anhydro-D-mannitol
about 6000 Da
Tinzaparin
Beta-eliminative cleavage
5500-7500 Da with a
2-O-sulpho-alpha-L-
2-N,6-O-disulpho-D-
(a sodium salt of LMWH)
by the heparinase enzyme
characteristic value of
idopyrano-suronic acid
glucosamine
about 6500 Da

Nadroparin
Nitrous acid depolymeri-
3600-5000 Da with a
2-O-sulpho-alpha-L-
6-O-sulpho-2,5-
(a calcium salt of LMWH)
zation of heparin
characteristic value of
idopyrano-suronic acid
anhydro-D-mannitol
followed by fractionation
about 4300 Da

to eliminate small chains



LMWHs are defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60
% of all chains have a
molecular weight less than 8000 Da. All currently available LMWHs are derived from porcine intestinal mucosa.


Table 2: Clinical efficacies of LMWHs concerning improved survival in cancer patients

LMWH assessed
Study
Result
Dalteparin
The CLOT study [16]
Improved survival in patients with good clinical
prognosis
Dalteparin
The FAMOUS study [17]
Significantly improved survival in the subgroup of
patients with good clinical prognosis
Nadroparin
The MALT study [18]
Improved survival in advanced cancer patients with
a life expectancy over 6 months
Nadroparin
Study on LMWH vs. unfractionated heparins for the treatment of
Improved survival of cancer patients in comparison
proximal deep vein thrombosis [72]
with patients receiving unfractionated heparins
Dalteparin
The North Central Cancer Treatment Group Randomization Office
No improvement regarding survival in patients with
[19]
advanced cancer
Tinzaparin
Study on LMWH vs. unfractionated heparins for the treatment of
Improved survival of cancer patients in comparison
proximal deep vein thrombosis in patients with cancer [73]
with patients receiving unfractionated heparins
Different LMWHs
Meta-analysis of 11 studies on LMWHs [74]
Improved survival of cancer patients in comparison
(meta-analysis)
with patients receiving unfractionated heparins



More detailed analysis of those trials has shown that in

Currently, the exact mechanism of the anti-metastatic
selected groups of cancer patients LMWHs improved
activity of heparins remains unclear. The protective effect
survival irrespective of anti-thrombotic efficacy, since
of heparins against metastases is unlikely to be a byproduct
vitamin K antagonists did not improve clinical prognosis.
of their anti-thrombotic activity. Most scientists claim that
Interestingly, this protective effect did not result from an
alternative mechanisms for this attenuation exist (Table 3).
inhibition of the growth of primary tumors, but rather from
Heparins are pleiotropic drugs and they can interact with a
prevention of the spreading of cancer through metastases
large number of biologically active glycans and glycopep-
[20,21]. This phenomenon has been also demonstrated in
tides that are thought to participate in cancer spreading and
some experiments on animals [22-24]. In addition, the
progression. Most likely, heparin-dependent attenuation of
protective effect of heparins was apparent only in some
metastases is secondary to a restraint of P- and L-selectin-
kinds of cancer, for example for small-cell lung cancer [25].
mediated interactions of platelets with circulating neoplastic
However, a complete list of heparin-susceptible cancers
cells [27-30], a modulation of the chemokine CXCL12/CXCR4
must still be established.
axis [31-33], an inhibition of heparanase activity [34-36], or
Consequently, two recently published meta-analyses
an inhibition of neo-angiogenesis in the tumor. Perhaps,
suggest that LMWHs added to the typical anti-cancer
this anti-metastatic action of heparins and heparin-related
therapy improve the survival of cancer patients, in particular
agents is due to the combined and summarized effect of the
those with non-metastatic disease, but perhaps even
above-described mechanisms and, maybe, some additional
patients with advanced tumors. The groups of patients who
ones that have yet to be discovered.
could particularly benefit from such a therapy, as well as
Still, findings from animal and in vitro experiments, even if
optimal dosing schedules, have yet to be established
they correspond to clinical observations of cancer patients,
[25,26].
are somewhat controversial. Experimental attenuation of
4                                                                                                                         Print ISSN 1816-0735; Online ISSN 1817-4256 
 

Anti-Metastatic Activities of Heparins 
Table 3: Evidence supporting the idea of anti-metastatic activities of LMWHs

Hypothesis
Results of clinical trials
Results of animal experiments and in vitro studies
Protective effect of heparins is dependent
Significantly improved survival of cancer
Anti-metastatic effect of LMWHs and their
on attenuation of cancer metastases
patients receiving LMWHs resulted from
derivatives proven in animal models of cancer
prevention of the spreading of cancer through
metastasis [22-24]
metastases [20,21]
Attenuation of metastases is dependent on
Data directly supporting the hypothesis
Selectin-specific heparin derivative attenuated
heparin-mediated inhibition of selectins
coming from clinical trials are lacking
metastasis in an experimental metastasis model [24];
similarly, absence of selectins improved survival in
an experimental metastasis model [38]
Attenuation of metastases is dependent on
Data directly supporting the hypothesis
LMWHs down-regulate CXCL12-CXCR4 signaling
heparin-mediated inhibition of the
coming from clinical trials are lacking
in laboratory (in vitro) settings [32,33,60]; data from
CXCL12-CXCR4 axis
animal experiments are lacking at the moment




metastases by heparins is routinely assessed by injection of

immunoglobulin in animal experiments decreased metasta-
cancer cells into the bloodstream of heparin-treated animals
ses of colon cancer to the lungs [44,45].
(usually mice) and subsequent evaluation of the number of
Selectins are C-type lectins that can interact with sialy-
neoplastic foci in the lungs and other organs. Moreover,
lated fucosylated ligands [46]. It has been demonstrated
mice are often injected with human cancer cells
that expression of sialylated fucosylated glycans by neo-
[22,27,28,33,37-40]. One may doubt, therefore, if this model
plastic cells is associated with an enhanced metastatic
actually represents the real spread of a tumor. It has been
potential in human cancers [27-30]. In animal models of
recently discovered that metastasis is not a simple dissemi-
metastasis, the spread of cancerous cells is facilitated by
nation of a primary tumor, but rather an orchestrated and
formation of selectin-mediated complexes, which consist of
complex process that requires collaboration of cancerous
neoplastic cells and platelets [28,37,40]. It has been found
cells with host tissues. Importantly, pre-metastatic niches in
that heparins inhibit the binding of P- and L-selectins to their
target organs should be previously “prepared” by the host
ligands, and many authors have argued that this inhibition is
immune cells to facilitate further successful metastasis [41].
the main mechanism by which heparins attenuate metasta-
The same uncertainties may also apply to the in vitro
ses [24,38]. It has been hypothesized that the selectin-
experiments, in which migration of cancerous cells through
dependent inhibition of metastases by heparins is primarily
an endothelial barrier or invasion into an extracellular matrix
executed through an interruption of platelet aggregates that
chamber was used to quantify the metastatic potential of
interact with leukocytes and cancerous cells (Figure 1). In
neoplastic cells [33,42]. Thus, probably, alternative experi-
animal models, inhibition of P- and L-selectins by heparin
mental models of cancer metastasis to test the inhibition of
correlated with inhibition of metastases [28]. Interestingly,
metastases should be developed.
this anti-metastatic effect was independent of the anticoagu-
Despite these controversies, heparins undoubtedly modu-
lant activity, and pentasaccharide (fondaparinux), a potent
late tumor spreading and this review presents the most
anticoagulant, has shown no anti-metastatic activity. In
likely mechanisms by which these drugs attenuate cancer
animal experiments, LMWHs differed in the level of inhibi-
metastases.
tion of metastases, and tinzaparin has been found to be

more efficient than dalteparin or enoxaparin [15]. Further-
Role for selectins in the inhibition of metastases
more, heparin derivatives with no anticoagulant activity
exhibited anti-metastatic properties similarly to LMWHs, and


this activity was also likely a result of an inhibition of P- and
Metastasis can be regarded as an active, multistep proc-
L-selectin-mediated interactions [38].
ess of migration of neoplastic cells, which is very similar to
the homing of leukocytes, although these processes differ in


some points [43]. The homing of a leukocyte includes: (i)
Role for the CXCL12-CXCR4 axis in the traffick-
rolling of a cell, which is mediated by selectins and their
ing of cancer stem cells
ligands (vascular addressins), (ii) exposure to chemotactic

stimulus, which is dependent on chemokines and G-protein-
According to current opinions, metastasis of cancer re-
coupled receptors, (iii) firm adhesion onto the endothelium,
sults from the directed migration of a specialized set of
which is mediated by activated integrins and their counter-
malignant cells, i.e., cancer stem cells. Cancer stem cells
parts, and (iv) migration across the endothelial barrier
represent a unique population of neoplastic cells. They
toward the gradient of chemokines. Different populations of
share several properties with normal tissue-derived stem
leukocytes precisely home to their target organs and tissues
cells. Both can be characterized as having a great prolifera-
because they are equipped with specialized sets of adhe-
tive potential, nearly unlimited capacity for self-renewal, and
sion molecules, chemokines, and their receptors. Corre-
a high resistance to apoptotic stimuli. Cancer stem cells are
spondingly, metastasis consists of the shedding of neoplas-
suspected to be resistant to conventional radiotherapy and
tic cells from the primary tumor, entering of these cells into
chemotherapy, and probably they can easily regenerate and
the circulation, and, similarly to leukocytes, docking to the
metastasize, making anti-cancer treatments ineffective [47-
endothelium in a new organ, followed by extravasation into
50].
the surrounding tissue [43]. This is a contemporary version
Probably, normal and cancer stem cells employ similar
of Pagetʼs “seed and soil” paradigm [44].
signaling molecules to regulate their migration [32]. It has
Migrating cancerous cells cannot survive for a long time
been found that at least some types of cancer, similarly to
in the circulation and unrestrained trafficking of these cells
primitive hematopoietic cells, use the CXCL12-CXCR4
to the target endothelium seems to be a critical point in
chemokine axis during trafficking (metastasizing) to target
successful metastasis. Any substance that disturbs this
organs [43,51,52]. This axis consists of CXCL12 (also called
process could potentially decrease the metastatic potential
SDF-1, stromal cell-derived factor-1), a chemokine that is
of a tumor. Since selectins participate in the first step of
known to be released by organs preferentially affected by
docking of neoplastic cells, interfering with selectin-
metastases (lymph nodes, bones, lungs, and liver), and
dependent rolling could inhibit metastasis at a very early
CXCR4, a chemokine receptor that is commonly expressed
stage. Indeed, inhibition of E-selectin with anti-E-selectin
by neoplastic cells in neuroblastoma, multiple myeloma,
© 2009 MedUnion Press http://www.mupnet.com                                                                                                                    5 

Simka & Urbanek. J Cancer Mol 5(1): 3-8, 2009













Figure 1: The most likely mecha-
nisms by which heparins attenuate
cancer metastases: A – inhibition of
selectin-dependent rolling of neoplas-
tic cells; B – inhibition of selectin-
dependent formation of complexes
composed of neoplastic cells and
platelets; C – inhibition of chemotaxis
mediated by the chemokine CXCL12-
CXCR4 axis; D – inhibition of hepara-
nase-dependent

degrading
of
basement membranes; E – inhibition
of neoangiogenesis in the tumor.





breast,

ovarian,
prostate,
and
pancreatic
cancers
found to decrease the activity of heparanase, which is not a
[42,43,53,55-58]. Thus, disruption of the CXCL12-CXCR4
ubiquitous phenomenon. Yet, heparin seems to reduce
signaling pathway could lead to a decrease of metastases
metastases through inhibition of heparanase only in the
[39]. It has been revealed that, in addition to other chemical
tumors where produce heparanase [24]. Thus, this inhibi-
compounds, heparins, primarily LMWHs, down-regulate
tion of heparanase is not believed to be the main mecha-
CXCL12-CXCR4 signaling [32,33,39,59-61](Figure 1). It has
nism of anti-metastatic action of heparins.
been postulated that dimerization of the CXCL12 could be

responsible for this effect [61-63]; yet, the exact mechanism
Inhibition of angiogenesis
of this inhibition is not known precisely. In addition to the
fact that the CXCL12-CXCR4 axis promotes metastases of


several types of cancer [64], it has been demonstrated that
Inhibition of angiogenesis deprives tumors of the blood
degradation of CXCL12 at the site of the primary tumor
necessary for their growth. LMWHs, in addition to their anti-
initiates the metastasis of prostate cancer [65]. Thus, the
thrombotic properties, also exhibit anti-angiogenic proper-
mechanisms involving CXCL12 and CXCR4 in the spread of
ties [67,68]. This inhibition of angiogenesis is mediated by
tumors are far more complex. Nevertheless, inhibition of
the release of an endothelial tissue factor pathway inhibitor.
the CXCL12-CXCR4 axis in selected groups of cancer
Moreover, the anti-angiogenic properties of heparin could
patients by heparins or heparin-related substances could be
also be related to the inhibition of heparanase, an enzyme
a very promising issue, as potentially it would target the
that is known to release angiogenic factors from the ex-
migration of cancer stem cells [31].
tracellular matrix [14,35,66,69]. LMWHs could also inhibit

angiogenesis in a tumor through suppression of VEGF
(vascular endothelial growth factor), a potent pro-angiogenic

Inhibition of heparanase
growth factor, since short heparin fragments have been

shown to inhibit the binding of VEGF to its receptors on
Heparanase is an endoglycosidase that degrades heparin
endothelial cells [70]. However, these in vitro findings of the
sulfate, one of the main components of the extracellular
anti-angiogenic action of LMWHs should be proven in
matrix. Heparanase is the essential enzyme that is respon-
clinical settings. Since LMWH administration exhibits only a
sible for degrading basement membranes, the process that
limited effect on the growth of primary tumors, an inhibition
is required for entrance of a metastasizing cell into the
of angiogenesis is unlikely to be the main anti-cancer action
bloodstream and also for the extravasation of such a cell to
of these drugs.
the target tissue. In addition, inhibition of heparanase could

exhibit an anti-angiogenic effect [4,14,35,66]. It has been
found that increased expression of heparanase by tumor

Future perspectives
cells correlated with a higher metastatic potential. There-

fore, heparanase-blocking substances could be potentially
Heparins are a group of pleiotropic drugs that significantly
useful in the treatment of cancer [34-36]. Heparin has been
influence different aspects of the biology of neoplastic
6                                                                                                                         Print ISSN 1816-0735; Online ISSN 1817-4256 
 

Anti-Metastatic Activities of Heparins 
tumors their prothrombotic activity, but also metastatic
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