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Cancer and Metastasis Reviews
Published in: Cancer and Metastasis Reviews 4/2010

Open Access 01-12-2010 | NON-THEMATIC REVIEW

Malignant melanoma as a target malignancy for the study of the anti-metastatic properties of the heparins

Authors: Anthony Maraveyas, Miriam J. Johnson, Yu Pei Xiao, Simon Noble

Published in: Cancer and Metastasis Reviews | Issue 4/2010

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Abstract

The outlook for metastatic melanoma to the brain is dismal. New therapeutic avenues are therefore needed. The anti-metastatic mechanisms that may underpin the effects of low molecular weight heparins (LMWHs) in in vitro and preclinical melanoma models warrant translating to a clinical setting. This review outlines a rationale that supports our proposal that metastatic melanoma to the brain is a clinical setting in which to study the anti-metastatic potential of LMWHs. Prevention or delay of brain metastases in melanoma is a clinically relevant and measurable target. Studies to explore the effect of anticoagulants on cancer survival are underway in other malignancies such as lung, pancreas, ovary, breast, and stomach cancer. However, no study to our knowledge has a methodology that could produce clinical evidence in support of a mechanism for whatever benefit may be seen. The setting we propose would allow translation of the molecular knowledge of the metastatic pathways mediated by platelets and the selectins—all potential targets of heparin—in a “time to appearance” of brain metastases endpoint. Since brain metastases are so common and they have a singularly adverse impact on survival, the “biological neuroprotection” model we propose in metastatic melanoma could provide the translational evidence to support the benefit of LMWHs in melanoma. More significantly, this would open the door to a wider “anti-metastatic” approach that could have much greater impact in patients with minimal disease being treated in adjuvant settings for the more common malignancies such as breast and colon cancer.
Literature
1.
Sgouros, J., & Maraveyas, A. (2008). Excess premature (3-month) mortality in advanced pancreatic cancer could be related to fatal vascular thromboembolic events. A hypothesis based on a systematic review of phase III chemotherapy studies in advanced pancreatic cancer. Acta Oncológica, 47(3), 337–346.CrossRefPubMed
2.
Chew, H. K., Wun, T., Harvey, D., Zhou, H., & White, R. H. (2006). Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Archives of Internal Medicine, 166(4), 458–464.CrossRefPubMed
3.
Altinbas, M., Coskun, H. S., Er, O., Ozkan, M., Eser, B., Unal, A., et al. (2004). A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. Journal of Thrombosis and Haemostasis, 2(8), 1266–1271.CrossRefPubMed
4.
Slotman, B., Faivre-Finn, C., Kramer, G., Rankin, E., Snee, M., Hatton, M., et al. (2007). Prophylactic cranial irradiation in extensive small-cell lung cancer. The New England Journal of Medicine, 357(7), 664–672.CrossRefPubMed
5.
Douglas, J. G., & Margolin, K. (2002). The treatment of brain metastases from malignant melanoma. Seminars in Oncology, 29(5), 518–524.CrossRefPubMed
6.
Wen, P. Y., Black, P. M., & Joeffler, S. L. (2001). Treatment of metastatic cancer. In V. T. Devita, S. Hellman, & S. A. Rosenberg (Eds.), Cancer: principles and practice of oncology (6th ed., pp. 2655–2670). Philadelphia: Lippincott, Williams & Wilkins.
7.
Barnholtz-Sloan, J. S., Sloan, A. E., Davis, F. G., Vigneau, F. D., Lai, P., & Sawaya, R. E. (2004). Incidence proportions of brain metastases in patients diagnosed (1973–2001) in the Metropolitan Detroit Cancer Surveillance System. Journal of Clinical Oncology, 22(14), 2865–2872.CrossRefPubMed
8.
Amer, M. H., Al-Sarraf, M., Baker, L. H., & Vaitkevicius, V. K. (1978). Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer, 42(2), 660–668.CrossRefPubMed
9.
Budman, D. R., Camacho, E., & Wittes, R. E. (1978). The current causes of death in patients with malignant melanoma. European Journal of Cancer, 14(4), 327–330.PubMed
10.
Bullard, D. E., Cox, E. B., & Seigler, H. F. (1981). Central nervous system metastases in malignant melanoma. Neurosurgery, 8(1), 26–30.CrossRefPubMed
11.
Patel, J. K., Didolkar, M. S., Pickren, J. W., & Moore, R. H. (1978). Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. American Journal of Surgery, 135(6), 807–810.CrossRefPubMed
12.
Avril, M. F., Aamdal, S., Grob, J. J., Hauschild, A., Mohr, P., Bonerandi, J. J., et al. (2004). Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. Journal of Clinical Oncology, 22(6), 1118–1125.CrossRefPubMed
13.
Middleton, M. R., Grob, J. J., Aaronson, N., Fierlbeck, G., Tilgen, W., Seiter, S., et al. (2000). Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. Journal of Clinical Oncology, 18(1), 158–166.PubMed
14.
Partridge, M. A., & Marcantonio, E. E. (2006). Initiation of attachment and generation of mature focal adhesions by integrin-containing filopodia in cell spreading. Molecular Biology of the Cell, 17(10), 4237–4248.CrossRefPubMed
15.
Fidler, I. J. (1970). Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125i-5-iodo-2′- deoxyuridine. Journal of the National Cancer Institute, 45(4), 773–782.PubMed
16.
Bromberg, M. E., Konigsberg, W. H., Madison, J. F., Pawashe, A., & Garen, A. (1995). Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proceedings of the National Academy of Sciences of the United States of America, 92(18), 8205–8209.CrossRefPubMed
17.
Honn, K. V., Tang, D. G., & Crissman, J. D. (1992). Platelets and cancer metastasis: a causal relationship? Cancer and Metastasis Reviews, 11(3–4), 325–351.CrossRefPubMed
18.
Gasic, G. J. (1984). Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer and Metastasis Reviews, 3(2), 99–114.CrossRefPubMed
19.
Karpatkin, S., & Pearlstein, E. (1981). Role of platelets in tumor cell metastases. Annals of Internal Medicine, 95(5), 636–641.PubMed
20.
Palumbo, J. S., Talmage, K. E., Massari, J. V., La Jeunesse, C. M., Flick, M. J., Kombrinck, K. W., et al. (2005). Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood, 105(1), 178–185.CrossRefPubMed
21.
Nash, G. F., Turner, L. F., Scully, M. F., & Kakkar, A. K. (2002). Platelets and cancer. The Lancet Oncology, 3(7), 425–430.CrossRefPubMed
22.
Jurasz, P., Alonso-Escolano, D., & Radomski, M. W. (2004). Platelet–cancer interactions: mechanisms and pharmacology of tumour cell-induced platelet aggregation. British Journal of Pharmacology, 143(7), 819–826.CrossRefPubMed
23.
Nieswandt, B., Hafner, M., Echtenacher, B., & Mannel, D. N. (1999). Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Research, 59(6), 1295–1300.PubMed
24.
Varon, D., & Brill, A. (2001). Platelets cross-talk with tumor cells. Haemostasis, 31(Suppl 1), 64–66.PubMed
25.
Baj-Krzyworzeka, M., Majka, M., Pratico, D., Ratajczak, J., Vilaire, G., Kijowski, J., et al. (2002). Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Experimental Hematology, 30(5), 450–459.CrossRefPubMed
26.
Varki, N. M., & Varki, A. (2002). Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans. Seminars in Thrombosis and Hemostasis, 28(1), 53–66.CrossRefPubMed
27.
Browder, T., Folkman, J., & Pirie-Shepherd, S. (2000). The hemostatic system as a regulator of angiogenesis. The Journal of Biological Chemistry, 275(3), 1521–1524.CrossRefPubMed
28.
Fischer, E. G., Ruf, W., & Mueller, B. M. (1995). Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells. Cancer Research, 55(8), 1629–1632.PubMed
29.
Melnikova, V. O., Villares, G. J., & Bar-Eli, M. (2008). Emerging roles of PAR-1 and PAFR in melanoma metastasis. Cancer Microenvironment, 1(1), 103–111.CrossRefPubMed
30.
Tellez, C., & Bar-Eli, M. (2003). Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Oncogene, 22(20), 3130–3137.CrossRefPubMed
31.
Mueller, B. M., Reisfeld, R. A., Edgington, T. S., & Ruf, W. (1992). Expression of tissue factor by melanoma cells promotes efficient hematogenous metastasis. Proceedings of the National Academy of Sciences of the United States of America, 89(24), 11832–11836.CrossRefPubMed
32.
Shi, X., Gangadharan, B., Brass, L. F., Ruf, W., & Mueller, B. M. (2004). Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Molecular Cancer Research, 2(7), 395–402.PubMed
33.
Bromberg, M. E., Bailly, M. A., & Konigsberg, W. H. (2001). Role of protease-activated receptor 1 in tumor metastasis promoted by tissue factor. Thrombosis and Haemostasis, 86(5), 1210–1214.PubMed
34.
Bar-Eli, M. (1999). Role of AP-2 in tumor growth and metastasis of human melanoma. Cancer and Metastasis Reviews, 18(3), 377–385.CrossRefPubMed
35.
Silini, A., Ghilardi, C., Ardinghi, C., Bernasconi, S., Oliva, P., Carraro, F., et al. (2010). Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype. Clinical & Experimental Metastasis, 27(1), 43–53.CrossRef
36.
Massi, D., Naldini, A., Ardinghi, C., Carraro, F., Franchi, A., Paglierani, M., et al. (2005). Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma. Human Pathology, 36(6), 676–685.CrossRefPubMed
37.
Villares, G. J., Zigler, M., Wang, H., Melnikova, V. O., Wu, H., Friedman, R., et al. (2008). Targeting melanoma growth and metastasis with systemic delivery of liposome-incorporated protease-activated receptor-1 small interfering RNA. Cancer Research, 68(21), 9078–9086.CrossRefPubMed
38.
Melnikova, V. O., & Bar-Eli, M. (2009). Inflammation and melanoma metastasis. Pigment Cell & Melanoma Research, 22(3), 257–267.CrossRef
39.
Borsig, L., Wong, R., Feramisco, J., Nadeau, D. R., Varki, N. M., & Varki, A. (2001). Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proceedings of the National Academy of Sciences of the United States of America, 98(6), 3352–3357.CrossRefPubMed
40.
Koop, S., MacDonald, I. C., Luzzi, K., Schmidt, E. E., Morris, V. L., Grattan, M., et al. (1995). Fate of melanoma cells entering the microcirculation: over 80% survive and extravasate. Cancer Research, 55(12), 2520–2523.PubMed
41.
Weiss, L. (1994). Inefficiency of metastasis from colorectal carcinomas. Relationship to local therapy for hepatic metastasis. Cancer Treatment and Research, 69, 1–11.PubMed
42.
Stevenson, J. L., Choi, S. H., & Varki, A. (2005). Differential metastasis inhibition by clinically relevant levels of heparins—correlation with selectin inhibition, not antithrombotic activity. Clinical Cancer Research, 11(19 Pt 1), 7003–7011.CrossRefPubMed
43.
Koenig, A., Norgard-Sumnicht, K., Linhardt, R., & Varki, A. (1998). Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. Journal of Clinical Investigation, 101(4), 877–889.CrossRefPubMed
44.
Stevenson, J. L., Varki, A., & Borsig, L. (2007). Heparin attenuates metastasis mainly due to inhibition of P- and L-selectin, but non-anticoagulant heparins can have additional effects. Thrombosis Research, 120(Suppl 2), S107–S111.CrossRefPubMed
45.
Ramsay, A. G., Marshall, J. F., & Hart, I. R. (2007). Integrin trafficking and its role in cancer metastasis. Cancer and Metastasis Reviews, 26(3–4), 567–578.CrossRefPubMed
46.
Fritzsche, J., Simonis, D., & Bendas, G. (2008). Melanoma cell adhesion can be blocked by heparin in vitro: suggestion of VLA-4 as a novel target for antimetastatic approaches. Thrombosis and Haemostasis, 100(6), 1166–1175.PubMed
47.
Zhang, C., Liu, Y., Gao, Y., Shen, J., Zheng, S., Wei, M., et al. (2009). Modified heparins inhibit integrin alpha(IIb)beta(3) mediated adhesion of melanoma cells to platelets in vitro and in vivo. International Journal of Cancer, 125(9), 2058–2065.CrossRef
48.
Lydolph, M. C., Morgan-Fisher, M., Hoye, A. M., Couchman, J. R., Wewer, U. M., & Yoneda, A. (2009). Alpha9beta1 integrin in melanoma cells can signal different adhesion states for migration and anchorage. Experimental Cell Research, 315(19), 3312–3324.CrossRefPubMed
49.
Witz, I. P. (2008). The selectin–selectin ligand axis in tumor progression. Cancer and Metastasis Reviews, 27(1), 19–30.CrossRefPubMed
50.
Fu, J., Naren, A. P., Gao, X., Ahmmed, G. U., & Malik, A. B. (2005). Protease-activated receptor-1 activation of endothelial cells induces protein kinase Calpha-dependent phosphorylation of syntaxin 4 and Munc18c: Role in signaling p-selectin expression. The Journal of Biological Chemistry, 280(5), 3178–3184.CrossRefPubMed
51.
Kansas, G. S. (1996). Selectins and their ligands: current concepts and controversies. Blood, 88(9), 3259–3287.PubMed
52.
53.
Kim, Y. J., Borsig, L., Varki, N. M., & Varki, A. (1998). P-selectin deficiency attenuates tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 95(16), 9325–9330.CrossRefPubMed
54.
Lee, D. Y., Park, K., Kim, S. K., Park, R. W., Kwon, I. C., Kim, S. Y., et al. (2008). Antimetastatic effect of an orally active heparin derivative on experimentally induced metastasis. Clinical Cancer Research, 14(9), 2841–2849.CrossRefPubMed
55.
Ludwig, R. J., Schon, M. P., & Boehncke, W. H. (2007). P-selectin: a common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis. Expert Opinion on Therapeutic Targets, 11(8), 1103–1117.CrossRefPubMed
56.
Ludwig, R. J., Alban, S., Bistrian, R., Boehncke, W. H., Kaufmann, R., Henschler, R., et al. (2006). The ability of different forms of heparins to suppress P-selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo. Thrombosis and Haemostasis, 95(3), 535–540.PubMed
57.
Kim, Y. J., Borsig, L., Han, H. L., Varki, N. M., & Varki, A. (1999). Distinct selectin ligands on colon carcinoma mucins can mediate pathological interactions among platelets, leukocytes, and endothelium. The American Journal of Pathology, 155(2), 461–472.PubMed
58.
Fuster, M. M., & Esko, J. D. (2005). The sweet and sour of cancer: glycans as novel therapeutic targets. Nature Reviews. Cancer, 5(7), 526–542.CrossRefPubMed
59.
Marshall, B. T., Long, M., Piper, J. W., Yago, T., McEver, R. P., & Zhu, C. (2003). Direct observation of catch bonds involving cell-adhesion molecules. Nature, 423(6936), 190–193.CrossRefPubMed
60.
Evans, E., Leung, A., Heinrich, V., & Zhu, C. (2004). Mechanical switching and coupling between two dissociation pathways in a P-selectin adhesion bond. Proceedings of the National Academy of Sciences of the United States of America, 101(31), 11281–11286.CrossRefPubMed
61.
Ludwig, R. J., Boehme, B., Podda, M., Henschler, R., Jager, E., Tandi, C., et al. (2004). Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Research, 64(8), 2743–2750.CrossRefPubMed
62.
Hejna, M., Raderer, M., & Zielinski, C. C. (1999). Inhibition of metastases by anticoagulants. Journal of the National Cancer Institute, 91(1), 22–36.CrossRefPubMed
63.
Akl, E. A., van Doormaal, F. F., Barba, M., Kamath, G., Kim, S. Y., Kuipers, S., et al. (2007). Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database of Systematic Reviews, 3, CD006652.
64.
Lebeau, B., Chastang, C., Brechot, J. M., Capron, F., Dautzenberg, B., Delaisements, C., et al. (1994). Subcutaneous heparin treatment increases survival in small cell lung cancer. “Petites Cellules” Group. Cancer, 74(1), 38–45.CrossRefPubMed
65.
Zacharski, L. R., Henderson, W. G., Rickles, F. R., Forman, W. B., Cornell, C. J., Jr., Forcier, R. J., et al. (1984). Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck, and prostate. Final report of VA Cooperative Study #75. Cancer, 53(10), 2046–2052.CrossRefPubMed
66.
Ornstein, D. L., & Zacharski, L. R. (2001). Treatment of cancer with anticoagulants: rationale in the treatment of melanoma. International Journal of Hematology, 73(2), 157–161.CrossRefPubMed
67.
Ma, Y. Q., & Geng, J. G. (2000). Heparan sulfate-like proteoglycans mediate adhesion of human malignant melanoma a375 cells to P-selectin under flow. Journal of Immunology, 165(1), 558–565.
68.
Wei, M., Gao, Y., Tian, M., Li, N., Hao, S., & Zeng, X. (2005). Selectively desulfated heparin inhibits P-selectin-mediated adhesion of human melanoma cells. Cancer Letters, 229(1), 123–126.CrossRefPubMed
69.
Hostettler, N., Naggi, A., Torri, G., Ishai-Michaeli, R., Casu, B., Vlodavsky, I., et al. (2007). P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins. The FASEB Journal, 21(13), 3562–3572.CrossRefPubMed
70.
Schlesinger, M., Simonis, D., Schmitz, P., Fritzsche, J., & Bendas, G. (2009). Binding between heparin and the integrin VLA-4. Thrombosis and Haemostasis, 102(5), 816–822.PubMed
71.
Niers, T. M., Bruggemann, L. W., Klerk, C. P., Muller, F. J., Buckle, T., Reitsma, P. H., et al. (2009). Differential effects of anticoagulants on tumor development of mouse cancer cell lines b16, k1735 and ct26 in lung. Clinical & Experimental Metastasis, 26(3), 171–178.CrossRef
Metadata
Title
Malignant melanoma as a target malignancy for the study of the anti-metastatic properties of the heparins
Authors
Anthony Maraveyas
Miriam J. Johnson
Yu Pei Xiao
Simon Noble
Publication date
01-12-2010
Publisher
Springer US
Published in
Cancer and Metastasis Reviews / Issue 4/2010
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-010-9263-y

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