Sir,
We enjoyed the recent articles on cancer-associated thrombosis and wish to comment on the attempts to explain the beneficial effects of heparin in cancer (Noble and Pasi, 2010; Kakkar and Macbeth, 2010).
Cited evidence indicates that the survival benefit of heparin in cancer is unexplained by venous thromboembolism (VTE) prophylaxis alone; unlike warfarin, heparin improves survival in cancer patients without VTE (Zielinski and Hejna, 2000; Cunningham et al, 2009). Alternative explanations independent of VTE prophylaxis include regulation of tissue factor and FVIIa with the TF–VIIa complex (Boccaccio and Comoglio, 2005; Rickles and Falanga, 2009), inhibition of cancer micrometastasis by blocking platelet and cancer cell aggregation (Borsig et al, 2001), and disruption of host wound-healing responses (including clotting and fibrin deposition) proposed to facilitate construction of tumour microenvironment (Dvorak, 1986). Although these explanations do not require VTE prophylaxis, they still relate to heparin's clotting-related effects.
Heparin is a multifunctional, highly sulphated form of heparan sulphate (HS), a member of the glycosaminoglycan family. Given the vast interactome of HS and related heparins (Ori et al, 2008), it is unsurprising that heparin's benefit in cancer cannot be linked solely to its anti-coagulant activity (Fuster and Esko, 2005; Escobar Galvis et al, 2007). Estimated to carry far more information than nucleic acids, the HS family are ubiquitous, varied and highly complex regulators of normal organogenesis (e.g., through growth factor modulation) with pleiotropic biological effects unrelated to anti-coagulation (Bishop and Schuksz Esko, 2007). Likewise, heparin has diverse, structure-related biological properties, only one of which is anti-coagulation and this can be manipulated through judicious structural modification to generate low-molecular-weight derivatives with improved selectivity (Norrby, 1993). Clinicians glimpsed heparin's diversity during replacement of unfractionated heparins with fractionated low-molecular-weight alternatives (although the focus remained anti-coagulation).
If they are entirely anti-coagulant related, further exploitation of heparin's benefits in cancer is inevitably limited by haemorrhage risk. However, by separating anti-coagulant from other bioactivities, ‘engineered’ (selectively modified) heparins provide the means to test whether heparins mediate their benefits in cancer independently of coagulation effects, as has been achieved for other biological activities such as inhibition of β-secretase or blood cell rosetting in malaria (Patey et al, 2006; Yates et al, 1996; Skidmore et al, 2008). Such developments offer the prospect of screening and developing a broad new class of anti-cancer heparins that can be used at optimum anti-tumour levels while retaining ameliorated anti-thrombotic activity.
Change history
29 March 2012
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Bishop JR, Schuksz Esko JD (2007) Heparan sulphate proteoglycans fine-tune physiology. Nature 446: 1030–1037
Boccaccio C, Comoglio PM (2005) A functional role for hemostasis in early cancer development. Cancer Res 65: 8579–8582
Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A (2001) Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci USA 98: 3352–3357
Cunningham MS, Preston RJ, O’Donnell JS (2009) Does antithrombotic therapy improve survival in cancer patients? Blood Rev 3: 129–135
Dvorak HF (1986) Tumors: wounds that do not heal. NEJM 315: 1650–1659
Escobar Galvis ML, Jia J, Zhang X, Jastrebova N, Spillmann D, Gottfridsson E, van Kuppevelt TH, Zcharia E, Vlodavsky I, Lindahl U, Li JP (2007) Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate. Nat Chem Biol 3: 773–778
Fuster MM, Esko JD (2005) The sweet and sour of cancer: glycans as novel therapeutic targets. Nat Rev Cancer 5 (7): 526–542
Kakkar AK, Macbeth F (2010) Antithrombotic therapy and survival in patients with malignant disease. Br J Cancer 102: S24–S29
Noble S, Pasi J (2010) Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer 102: S2–S9
Norrby K (1993) Heparin and angiogenesis: a low-molecular-weight fraction inhibits and a high-molecular-weight fraction stimulates angiogenesis systemically. Haemostasis Suppl 1: 141–149
Ori A, Wilkinson MC, Fernig DG (2008) The heparanome and regulation of cell function: structures, functions and challenges. Front Biosci 13: 4309–4338
Patey SJ, Edwards EA, Yates EA, Turnbull JE (2006) Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases. J Med Chem 49: 6129–6132
Rickles FR, Falanga A (2009) Activation of clotting factors in cancer. Cancer Treat Res 148: 31–41
Skidmore MA, Dumax-Vorzet AF, Guimond SE, Rudd TR, Edwards EA, Turnbull JE, Craig AG, Yates EA (2008) Disruption of rosetting in Plasmodium falciparum malaria with chemically modified heparin and low molecular weight derivatives possessing reduced anticoagulant and other serine protease inhibition activities. J Med Chem 51: 1453–1458
Yates EA, Santini F, Guerrini M, Naggi A, Torri G, Casu B (1996) 1H and 13C NMR spectral assignments of the major sequences of twelve systematically modified heparin derivatives. Carbohydr Res 294: 15–27
Zielinski CC, Hejna M (2000) Warfarin for cancer prevention. N Engl J Med 342: 1991–1993
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Solari, V., Jesudason, E., Turnbull, J. et al. Determining the anti-coagulant-independent anti-cancer effects of heparin. Br J Cancer 103, 593–594 (2010). https://doi.org/10.1038/sj.bjc.6605808
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6605808