Journal of Thrombosis and Haemostasis, 5 (Suppl. 1): 246–254
INVITED REVIEW
Cancer and thrombosis: from molecular mechanisms to clinical presentations H . R . B U L L E R , F . F . V A N D O O R M A A L , G . L . V A N S L U I S and P . W . K A M P H U I S E N Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands
To cite this article: Buller HR, Van Doormaal FF, Van Sluis GL, Kamphuisen PW. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 5 (Suppl. 1): 246–54.
Summary. Although the bidirectional association between cancer and venous thromboembolism (VTE) has been known for almost two centuries, recent advances in our understanding of the clinical, laboratory, and epidemiologic aspects of this association have created a renewed interest in this topic. This review consists of two parts. The first part discusses the occurrence, determinants and significance of VTE in those with cancer, as well as the risk of developing and the possible need to detect cancer in those presenting with VTE. The second part reviews the role of hemostatic constituents (coagulation and fibrinolytic proteins and platelets) in promoting growth and progression of cancer, as well as the effects and possible mechanisms of the low molecular weight heparins (LMWH) in this process. Keywords: cancer, (low molecular weight) heparins, hemostasis, venous thromboembolism.
Cancer and thrombosis Historically, Armand Trousseau, the French physician (1801– 1867), is often considered to have been the first scientist to describe the association between cancer and venous thrombosis. This is incorrect for both the relationship of cancer with subsequent complicating VTE as well as for occult cancer in thrombosis patients. A careful literature analysis revealed that already in 1823 Bouillaud described three cancer patients with deep venous thrombosis [1,2]. He speculated in his monogram that the peripheral edema in the legs of these cancer patients was the result of obstruction of the veins by Ôcaillot fibrineuxÕ (fibrin clots) induced by the cancer process. Trousseau was 22 years old at that time. In the frequently quoted book by Trousseau, published in 1865, he indeed described in detail the Correspondence: Harry R. Buller, Department of Vascular Medicine, Academic Medical Center, Room F4-211, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Tel.: +31 205 665 9765; Fax.: +31 206 968 833 e-mail: m.m.veendorp@amc.uva.nl Received 14 February 2007, accepted 21 February 2007
relationship between cancer and VTE, but that was 42 years after Bouillaud [3]. Trousseau is also often quoted for the link between venous thrombosis and occult cancer. Close reading of his papers reveal that all his patients described with VTE already had extensive evidence of cancer at the time of the diagnosis of thrombosis [4,5]. The honor of the first description of a patient with deep venous thrombosis and the manifestation of a gastric cancer several months later goes to Illtyd James and Matheson [6]. They published their paper in 1935. Interestingly, the first proper cohort study in patients with VTE to assess the incidence of occult cancer was only published in 1982 [7]. These authors coined the question of whether an extensive search for cancer at the time of VTE diagnosis was indicated. The focus in this part of the review will be on deep vein thrombosis of the leg (DVT) or pulmonary embolism (PE) and the two-way association with cancer, with special emphasis on the epidemiologic aspects, the magnitude and consequences. Other manifestations of venous thrombosis, such as superficial flebitis, arm vein thrombosis, and catheter-related thrombosis, as well as the prevention and treatment of DVT and PE are outside the scope of this contribution.
Cancer and venous thromboembolism
In cancer patients VTE complications are common and the second leading cause of death [8–10]. Of every seven patients with cancer who die in hospital, one dies of pulmonary embolism [11]. Compared with non-cancer patients the risk of developing symptomatic VTE is six to seven times higher in cancer patients, with similar risks for the components of VTE (i.e. DVT and PE) [12,13]. The precise incidence and time course of VTE complications among cancer patients have until recently largely been unknown [14]. Initially, small cohort studies estimated the incidence among patients with various types and stages of cancer to be approximately 4% [14]. Subsequent larger epidemiologic studies found incidences of clinically manifest VTE of 110–120 events per 10 000 patients [15,16]. Recently, a large population-based study determined the incidence of VTE among patients diagnosed with specific types and stages of cancer [14]. Among 235 149 cancer cases, confirmed symptomatic VTE events were diagnosed within 2007 International Society on Thrombosis and Haemostasis
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2 years in 1.6%. Twelve percentage of these events occurred at the time cancer was diagnosed and the remaining 88% were observed subsequently. In another recent large populationbased study the duration between the diagnosis of cancer and the occurrence of VTE was determined [13]. In the first 3 months the risk of VTE was the highest, with an odds ratio of 54, whereas in the period between 3 and 12 months following the cancer diagnosis, the odds ratio of VTE was 14, and between 1 and 3 years this figure was 4 [13]. Table 1 details the determinants for the risk of symptomatic episodes of VTE in patients with cancer. In risk-adjusted models Chew and colleagues found metastatic disease at the time of cancer diagnosis the strongest predictor of VTE [14]. The risk was four to 13 times higher as compared with cases with localized disease. In patients with metastatic-stage disease the highest incidences (expressed as VTE events per 100 patient-years) were observed for pancreatic (20.0), stomach (10.7), bladder (7.9), uterine (6.4), renal (6.0), and lung (5.0) cancer. Most of the VTE complications occurred in the first year of follow-up [14]. Blom and colleagues also determined the significance of distant metastases for the risk of VTE and found an odds ratio of 20 as compared with patients without distant metastases [13]. All hematologic and solid tumor types have been associated with VTE. However, conflicting data exist about the relative risk of VTE according to tumor histology and site of primary location [8]. It is, however, clear that the VTE risk is not equal among the various types of cancer. Adjusted for age and sex, Blom et al. observed, in a population-based study, the highest risk of VTE among patients with hematological malignancies (odds ratio 28), followed by lung cancer (odds ratio 22) and gastrointestinal cancer (odds ratio 20) [13]. In another population-based study, Heit and colleagues noted that pancreatic cancer, lymphoma, and brain cancer have relative risks of VTE >25, followed by liver cancer, leukemia, and other gastrointestinal (esophagus, gallbladder) and gynecological cancer, with a relative risk above 17 [17]. In a study of hospitalized patients the highest incidence of VTE occurred among women with ovarian cancer, followed by brain and pancreas cancer and lymphoma [15,16]. The third and probably at present the most changing determinant for the risk of VTE is anticancer therapy (Table 1). Chemotherapy is a well-recognized independent risk factor for VTE and the annual incidence has been estimated to be 10%– 20% depending on the type of drugs given [8,18]. However, one Table 1 Determinants for the risk of venous thromboembolism in cancer patients Tumor stage Tumor type Anticancer therapy Chemotherapy Hormonal therapy Angiogenesis inhibitors Supportive therapy Surgery Prothrombotic abnormalities
2007 International Society on Thrombosis and Haemostasis
of the most prominent reasons for the increasing importance of anticancer therapy as a determinant for the thrombosis risk is that in addition to chemotherapy, other frequently combined therapies to treat the cancer, such as hormonal therapy, angiogenesis inhibitors, and supportive therapy, carry their own risk to induce a hypercoagulable state [8]. Probably the best-studied influence of chemotherapy on the risk of thrombosis is in patients with breast cancer. In early stage breast cancer the risk of VTE is similar to that in the general population (approximately 0.2%). With chemotherapy or hormonal treatment this increases to 1%–2%. When in stages I–II chemotherapy and hormonal therapy are combined the incidence rises to 5%–7% [8,19,20]. For patients with stage IV breast cancer these rates may be as high as 18% with the combined treatments [8]. Other chemotherapeutic agents, such as cisplatin (reported VTE rates of 8%–18%), L-asparaginase (reported VTE rates in adults of 4%–14%) and fluorouracil (reported VTE rates of 15%– 17%), often in combination with other forms of chemotherapy, have been clearly associated in retro and prospective studies with an increased risk of VTE [8]. Thalidomide, particularly in combination with dexamethasone or doxorubicin, may induce VTE rates as high as 20%–40% [8,21]. Whether the newer thalidomide analogs (IMiDs) really have lower VTE complication rates remains to be demonstrated, in particular when combined with other forms of chemotherapy. Initially, angiogenesis inhibitors (such as bevacizumab), again in combination with chemotherapy, were reported to induce higher rates of VTE, but more recent comparisons (with and without bevacizumab) suggest that the contribution of angiogenesis inhibitors may be marginal [8,22]. Finally, supportive therapies associated with an increased risk of VTE include erythropoietin, hemotopoietic colony-stimulating factors, and high-dose corticosteroids. Cancer patients undergoing surgical procedures have an approximately 2-fold higher risk of developing VTE as compared with non-cancer patients [12,23]. Incidences of symptomatic VTE within 91 days after the procedure in cancer patients were as high as 3%–4% for radical cystectomy, nephrostomy, brain surgery, and total hip replacement [23]. Other determinants of the VTE risk in cancer patients include the classical risk factors such as immobility, age, and also prothrombotic abnormalities. Carriers of the factor (F) V Leiden mutation who also had cancer had a 12-fold increased risk of developing VTE as compared with individuals with the mutation but no cancer [13]. This is in agreement with earlier observation and also applies to other genetic thrombophilias, such as the prothrombin mutation [13,24,25]. Cancer patients who have developed VTE have an approximately 3-fold higher risk of experiencing a recurrent thrombosis in the first 12 months as compared with VTE patients without cancer [12,15,26]. Prandoni and colleagues observed recurrent VTE in 6.8% of patients without cancer, whereas in those with cancer the incidence was 20.7% [26]. Developing VTE predicts a worse prognosis in cancer patients [15,27]. The 1-year survival was 12% in patients diagnosed with cancer and VTE at the same time, compared with 36% in cancer
1.00 DVT/PE and Malignant disease
Probability of death
0.80
0.60
Malignant disease 0.40 DVT/PE Only
0.20
Nonmalignant disease
0.00 0
20
40
60
80
100 120 140 160 180
Number of days Fig. 1. Probability of death within 183 days of initial hospital admission [15]. Reproduced with permission of the publisher.
patients without VTE in a population-based study [27]. Figure 1 shows the mortality rates in the first 180 days in patients with cancer and VTE, which are more than 2-fold higher than those in cancer patients without VTE [27]. Venous thromboembolism and cancer
In patients with symptomatic VTE, the incidence of concomitant cancer (i.e. cancer not known before the diagnosis of VTE and discovered by routine investigation) at the time of VTE diagnosis, varies in the larger studies between 4% and 12% [28]. The cancer stage in patients with concurrently diagnosed VTE is often advanced [27,29]. Furthermore, the risk of concomitant cancer is 3- to 4-fold increased in patients with idiopathic VTE compared with secondary VTE [28]. The risk of occult cancer (i.e. cancer that becomes clinically apparent during follow-up) is also increased in patients with VTE. Summarizing 17 cohort and two population-based studies, Otten and Prins calculated an incidence of new cancer in patients with idiopathic VTE of 4%–10%, diagnosed within 3 years after the thrombotic event [28]. Again, this incidence was higher in idiopathic VTE than in patients with secondary VTE. The incidence of cancer is the highest shortly after VTE has been diagnosed. During the first year, the standardized incidence ratio for cancer in patients with VTE is 2.1–4.6, while after this period the risk gradually decreases [30]. In the large Californian registry, White et al. showed that the incidence of cancer was the highest during the first 60 days after an unprovoked episode of VTE (Fig. 2), with a gradual
Total cases with venous thromboembolism
248 H. R. Buller et al 200
Observed
Expected
180 160 140 120 100 80 60 40 20 0
365–305 304–244 243–183 182–122 121–61 Days before diagnosis of cancer
60–0
Fig. 2. Timing of diagnosis of unprovoked venous thromboembolism events relative to the cancer diagnosis date, using 2-month (61-day) increments [29]. Reproduced with permission of the publisher.
decline afterwards [29]. In the first 4 months after VTE diagnosis, the standardized incidence ratio was 2-fold higher than the expected incidence, whereas the observed and expected incidences of cancer 4–12 months after VTE were virtually the same. Also the occurrence of metastasized disease was the highest in the first 4 months after an unprovoked VTE. This indicates that the risk of cancer is only increased in the first months to a year after a VTE, while many patients already have metastases. The risk of developing overt cancer after VTE also depends on the type of cancer. In the large Danish registry, Sørensen and colleagues showed that around 15% of the patients with VTE and cancer within 1 year had lung cancer, followed by prostate (11.4%), pancreas (7.9%), colon (7%), and breast (4.3%) cancer [27]. Leukemia and non-Hodgkin lymphoma were found in 2.5% of the patients [27]. In the Californian cancer registry, White et al. revealed the highest standardized incidence ratios for acute myelogenous leukemia (4.2), followed by ovarian cancer (2.8), non-Hodgkin lymphoma (2.7), pancreatic (2.6), renal cell (2.5), stomach and lung cancer (1.8) [29]. Considering the high incidence of cancer in the first months after VTE, screening for an underlying malignancy may be clinically relevant. The literature is, however, not concordant on whether extensive screening for occult malignancy is indicated. Retrospective studies indicated that a careful medical history, physical examination, and laboratory testing detected most occult cancers in patients with VTE [31–33], suggesting that routine examination at the time of VTE diagnosis is sufficient to detect most underlying malignancies and that additional testing would not be required. Prospective studies seem to indicate that extensive screening is able to detect more cancers than routine examination alone. The six prospective studies that systematically evaluated the added value of more extensive screening compared with routine examination are summarized in Fig. 3 [34–39]. Routine examination was in most studies defined as a combination of careful medical history taking, thorough physical examination, laboratory 2007 International Society on Thrombosis and Haemostasis
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Fig. 3. Detection of occult malignancy in patients with venous thromboembolism by routine screening alone or by routine screening followed by more extensive screening.
testing, and chest X-ray. In most studies, extensive testing included specific tumor markers, such as prostate-specific antigen, carcinoembryonic antigen, or cancer antigen-125 levels, and abdomino-pelvic ultrasonography. Upon indication, this screening was extended with CT-scanning of chest, abdomen or pelvis, gastro-, colono-, or sigmoidoscopy, mammography, or sputum cytology. In the six studies, routine testing followed by more extensive screening was associated with a 1.8-fold (95% CI: 1.28–2.51) higher probability of finding occult cancer, compared with routine testing alone (Fig. 3). The only randomized trial by Piccioli et al., however, found no additional value of extensive screening [38]. Furthermore, after routine screening the incidence of cancer showed a large variation in the different studies. This is likely to be due to differences in patient characteristics, but also to the type of routine screening itself. A predefined protocol focusing on the possibility of occult cancer that clearly describes history taking, physical examination, and laboratory testing is a prerequisite in order to reliably assess the additional value of extensive screening. In addition, another potential source of variation is the definition of extensive screening, which is not well defined. Finally, if extensive screening is advocated, early detection of cancer must lead to a benefit in survival, a matter that has not yet been adequately addressed. An ongoing study may soon provide more information. This multicenter study directly compares routine and extensive testing for occult malignancy in patients with VTE (The Trousseau study). Centers that only used routine testing, consisting of medical history, physical examination, basic laboratory examination, and chest X-ray, are compared with matched centers that additionally perform thoracic and abdominal CT, plus mammography in women. So far 444 patients have been included. The planned total number of patients is 1200. An interim analysis reveals that in the routine testing arm, 16 of 176 had a suspected cancer after the initial assessment, which was confirmed in one patient (0.6%, 95% CI: 0.2–3.1). During a median follow-up of 12 months, six new malignancies were diagnosed (incidence 3.4%, 95% CI: 1.3– 7.3). In the routine and additional screening arm, 30 of 268 patients were thought to have a malignancy after the initial assessment. In 11 patients a malignancy was diagnosed (4.1%, 95% CI: 2.1–7.2). Of these 268 patients, 214 underwent the additional screening tests. Follow-up diagnostic tests were ordered in 49 patients. In four a malignancy was found. During 2007 International Society on Thrombosis and Haemostasis
a median follow-up of 12 months, six new neoplasms were diagnosed (incidence 2.4%, 95% CI: 0.87–5.1) (abstract ISTH). Based on these preliminary data the additional value of CT screening appears to be limited in patients with idiopathic VTE. A standard initial assessment seems effective enough for diagnosing cancer in these patients. Cancer, hemostasis, and heparins This second part, first describes the way cancer cells utilize hemostatic constituents for their growth and progression. Recently, a rise in the interest in the association of cancer and thrombosis was driven by the discovery of potential anticancer effects of anticoagulants in particular heparins. The clinical effects of (LMW) heparins in cancer patients are summarized and the potential mechanisms of the anticancer effects of heparins are discussed. Other anticoagulants are outside the scope of this review. Hemostasis and cancer
Multiple pathways result in cancer growth and progression. Cancer cells gain capacity to proliferate, migrate, and induce proteolysis and permeability. They have a reduced sensitivity to apoptosis and develop functions of increased motility and adhesion [40]. It is now well established that the essential factors of hemostasis (e.g. coagulation and fibrinolytic proteins, and platelets), apart from their procoagulant effects, directly play a role in these processes. However, fibrin formation itself is essential as a supportive scaffold for angiogenesis that ensures the tumorÕs oxygen supply [41–43]. The effects and possible pathways through which the individual factors and their complexes work are summarized in Table 2. Tissue factor levels are associated with clinical progression of cancer and elevated levels are an unfavorable prognostic indicator. Tissue factor gene silencing can inhibit tumor growth and metastasis in vivo [44–46]. The importance of tissue factor for invasive growth is nicely illustrated by the fact that without tissue factor there can be no embryonic development [47]. The aberrant expression of tissue factor in cancer and vascular endothelial cells is stimulated by the tumor as a result of activation of the k-ras oncogene and loss of p53 tumor suppressor gene, as well as through inflammatory signals such as interleukine-1b and tumor necrosis factor-a [48]. These
250 H. R. Buller et al Table 2 The role of hemostatic constituents (coagulation and fibrinolytic proteins and platelets) in the growth and progression of cancer Hemostasis Coagulation proteins Specific interactions Tissue factor TF-FVIIa Factor Xa Thrombin
Pathway/mechanism
Effects on cancer growth and progression
VEGF expression› k-ras expression VEGF› TSPfl TF› Cancer procoagulant TF, VEGF, VEGFR, bFGF, MMP-2
Angiogenesis›, permeability› Metastasis, tumor growth Angiogenesis›, cell survival›, apoptosisfl Proliferation› Altered cell shape, proliferation›, permeability ›, migration›, cell survival›, proteolysis› Angiogenesis›, apoptosisfl
Platelets activation, growth factors release Mobilization of adhesion molecules Procoagulant interactions TF-FVIIa TF-FVIIa-FXa Fibrinolytic proteins u-PA, t-PA PAI-1, PAI-2 Platelets
Motility›
Thrombin/fibrin formation
Matrix for angiogenesis Feedback: TF expression›
Thrombin formation Proteolysis/fibrinolysis Fibrin matrix conservation
Invasion, proliferation Angiogenesis›
Release of growth factors (VEGF, PDGF, bFGF) P-selectin expression NK-cell protection (coating) COX-2›
Angiogenesis›, permeability›, apoptosisfl Tumor cell adhesion ›, migration› Tumor cell survival› Apoptosisfl
bFGF, basic fibroblast growth factor; COX-2, cyclo-oxygenase-2; NK-cell, natural killer cell; PAI-1, plasminogen activator inhibitor type 1; PDGF, platelet-derived growth factor; TF, tissue factor; t-PA, tissue type plasminogen activator; TSP-1, thrombospondin-1; TFPI, tissue factor pathway inhibitor; u-PA, urokinase plaminogen activator; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
cytokines also influence leukocyte, platelet, and endothelial cell function, resulting in decreased thrombomodulin expression on the endothelial cell surface, impairment of the protein C anticoagulant pathway and enhanced expression of adhesion molecules [46]. Furthermore, tissue factor (isolated as well as in complex with FVIIa) induces vascular-derived growth factor (VEGF) expression, down-regulation of thrombospondin and further tissue factor expression [49–52]. Together, this stimulates angiogenesis, adhesion, and migration [53,54]. The TF–FVIIa complex induces also survival of cells that have been directed toward apoptosis [55,56]. Cancer procoagulant, a cystein protease that is expressed on the surface of many cancer cells, can directly induce activation of FX independent of FVIIa. Hereby, vascular cell proliferation is promoted [46]. Thrombin enhances the expression of tissue factor, VEGF, VEGF-receptor, basic fibroblast growth factor, and matrix metalloproteinase through signaling via the protease activated receptors on the cell surface of cancer cells and/or vascular endothelial cells [57–61]. This leads to changes in endothelial cell shape and proliferation, increased vascular permeability, migration, and enhanced survival of cancer cells [54,62,63]. The factors mentioned above are all well known for their classic role in the hemostatic system, which naturally occurs at the same time. It appears that activating the coagulation system
has advantages for cancer growth and progression, as fibrin is an excellent matrix for angiogenesis. The fibrin matrix also protects against proteolysis. Furthermore, fibrin formation leads to proliferation and migration and in reverse to tissue factor expression, which is probably signaled through the proangiogenetic cytokine IL-8 [46,64,65]. The complex of tissue factor-FVIIa-FXa stays active because of impaired TFPI binding, which results in prothrombin conversion and thrombin formation [43]. Cancer cells can express many fibrinolytic proteins (uPA, tPA, PAI-1, PAI-2) and both promotion as well as inhibition occurs [66]. Cancer cells overall impair the fibrinolytic system, which results in fibrin matrix conservation, tumor invasion, cell proliferation, and metastasis. Activation of platelets by thrombin leads to release of growth factors such as VEGF, platelet-derived growth factor, and basic fibroblast growth factor. These growth factors contribute to angiogenesis and inhibit apoptosis [67,68]. Cancer cells enhance P-selectin expression on monocytes, macrophages, endothelial cells, and platelets [69]. In addition, cancer cells express P-selectin ligands to bind those cells. The latter provides protection against natural killer cells and therefore leads to tumor cell survival and enhanced adhesion to the endothelium [70]. Platelets promote COX-2 synthesis in monocytes and it has been shown that COX-2 overexpression leads to inhibited apoptosis, abnormal cell-to-cell interactions and a more 2007 International Society on Thrombosis and Haemostasis
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invasive phenotype. Furthermore, prostaglandins (COX-2 products and mediators of classic inflammation) might suppress host immunity against tumors [71,72]. More recently, coagulation system activation has been related to hypoxia driven overexpression or mutation of the MET-oncogene (physiologic invasive growth). Boccaccio and colleagues induced disseminated intravascular coagulation and the Trousseau syndrome by targeting the human METoncogene in the mouse liver, resulting in enhanced PAI-1 and COX-2 expression [73–75]. In glioblastomas it was found that a tumor suppressor gene (PTEN) and hypoxia-regulated tissue factor expression can induce intravascular thrombotic occlusion [76]. Cancer and heparins
For many decades, experimental and clinical studies have evaluated the effects of anticoagulants on tumor growth with different outcomes. In 1992, Prandoni et al. observed an important reduction in total mortality in the subgroup of VTE patients with cancer at enrolment that received LMWH. At 3 months, 44% (eight of 18) of the cancer patients died in the standard heparin group vs. 7% (one of 15) in the LMWH group (P = 0.021) [77]. These findings of a survival benefit of LMWH in cancer patients were confirmed in a meta-analysis of nine studies that compared LMWH with standard heparin in the treatment of VTE [78]. These results have led to clinical trials that evaluated the effect of (LMW) heparin on survival in cancer patients without thrombosis. Figure 4A presents the overall survival results at 6 months after study entry of the five randomized controlled trials that primarily evaluated the effects of (LMW) heparin on cancer progression [79–83]. Overall, there is no difference in survival (odds ratio 0.91; 95% CI: 0.71–1.16). These studies, however,
differ considerably in study design. In one study UFH was administered, in the others LMWH [79]. In two of the studies only patients with small cell lung cancer were included [79,80], whereas patients with different cancer types were enrolled in the other studies. The duration of heparin therapy differed, from 5 to 52 weeks. In one study a therapeutic dose of LMWH was given [82]. Three studies defined a priori a subgroup consisting of patients with a prognosis of at least 6 months at study entry (also referred to as limited disease) [79,80,82]. Figure 4B shows the survival in this subgroup. Patients treated with (LMW) heparin have a significant survival benefit (odds ratio 0.47; 0.30–0.75). Subgroup analysis indicated no benefit for patients with advanced disease (odds ratio 0.96; 0.77–1.21). Post hoc analyses of other studies are in agreement with these positive findings in those with limited disease [81,83,84]. These clinical results are supported by proposed mechanisms of heparin on cancer progression, mainly based on in vitro and in vivo studies. The possible mechanisms by which heparins impair cancer growth and progression include decrease of thrombin and fibrin formation, binding to adhesion molecules, antiheparanase effects and increase of apoptosis. Heparins have well-known anticoagulant effects resulting in inhibition of thrombin and fibrin formation. As discussed above, both thrombin and fibrin are important for cancer growth and progression. Besides its coagulant effects, heparin is thought to have other properties. This is illustrated by the antimetastatic effects of non-anticoagulant heparins [85]. The first non-anticoagulant mechanism of heparin is interfering with the interaction between cancer cells and platelets. Specific oligosaccharide structures in heparin can bind to P-selectins exposed on activated platelets [86]; these structures show minimal anticoagulant activity [87]. Ludwig and colleagues tested the impact of UFH, LMWH (nadroparine and enoxaparin), and fondaparinux on P-selectin-dependent tumor
A
B
Fig. 4. (A) Heparin vs. placebo or no anticoagulants in patients with cancer. Overall survival after 6 months. (B) Heparin vs. placebo or no anticoagulants in patients with cancer. Survival after 6 months in patients with limited disease, with a similar definition at study entry. UFH, unfractioned heparin; LMWH, low-molecular weight heparin. 2007 International Society on Thrombosis and Haemostasis
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interactions in vitro and metastasis formation in vivo. These agents differ widely in their potential to interfere with Pselectin-mediated cell binding. This inhibitory function strongly correlates with the potency in inhibiting experimental lung metastasis in vivo [88,89]. Selectins are also expressed on leukocytes (L-selectin) and the vascular endothelium (E- and Pselectin). Heparin can inhibit L-selectin binding to its ligands, resulting in inhibition of the inflammatory response. Extravasation of cancer cells is also hindered by binding of heparin to selectins. [86,90,91]. The second non-anticoagulant property of heparin is inhibition of cancer cell heparanase [92]. Heparanase is expressed in many human cancers. This enzyme breaks down the polysaccharide barrier, facilitating cancer-cell invasion through the vascular basement membrane; also angiogenesis and metastases are promoted [93]. In humans elevated heparanase expression by the tumor has been correlated with a more aggressive behavior in breast, colon, ovary, pancreas, non-small lung cancer, acute myeloid leukemia, and myeloma tumors [94–101]. Heparanase also cleaves the growth factor bearing heparan sulfate groups from heparan sulfate proteoglycans in the extracellular matrix and cellular membranes [102– 104]. Heparins can directly inhibit the effect of growth factors as well. LMWH hinders binding of growth factors to highaffinity receptors to a greater degree than UFH [105]. Heparin, especially LMWH, is thought to increase the apoptosis index in cancer cells. Nasir et al. observed in heparin knockout mice a 4-fold increase in the apoptosis index with LMWH as compared with controls [106]. Heparin probably enters the cell by endocytosis and induces apoptosis by interfering with transcription factor [107]. Disclosure of conflict of interest HRB has received grants from Sanofi-Aventis, GSK, and Bayer. The other authors have not declared any conflicts of interest. References 1 Bouillaud S. De lÕObliteration des veines et de son influence sur la formation des hydropisies partielles: consideration sur la hydropisies passive et general. Arch Gen Med 1823; 1: 188–204. 2 Otten HM. Thrombosis and cancer, Thesis, Academic Medical Center, University of Amsterdam, 2002. 3 Trousseau A. Phlegmasia alba dolens. In: Trousseau A, ed. Clinique medicinale de lÕHotel-Dieu de Paris. Paris: Bailliere J.-B. et fils, 1865: 645–712. 4 Trousseau A. Ulcere chronique simple de lÕestomac. In: Peter M, ed. Clinique Medicinale de lÕHotel-Dieu de Paris.Paris: Bailliere J.-B. et fils: 1877: p. 80–107. 5 Trousseau A. Phlegmasia alba dolens. In: Peter M, ed. Clinique Medicinale de lÕHotel-Dieu de Paris.Paris: Bailliere J.-B. et fils: 1877: p. 695–739. 6 Illtyd James T, Matheson N. Thromboplebitis in cancer. Practitioner 1935; 134: 683–4. 7 Gore JM, Appelbaum JS, Greene HL, Dexter L, Dalen JE. Occult cancer in patients with acute pulmonary embolism. Ann Intern Med 1982; 96: 556–60.
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