Platelets and Cancer: Implications for Antiangiogenic Therapy

 

 Buy Article Permissions and Reprints

ABSTRACT

Thromboembolism is one of the most common causes of death in cancer patients. Among the most frequent thrombotic complications in patients with cancer are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and thrombocytosis. Clearly, these complications arise as tumor cells interact with almost all components of the hemostatic system including platelets. Platelets participate in tumor progression by contributing to the metastatic cascade, protecting tumor cells from immune surveillance, regulating tumor cell invasion, and angiogenesis. Platelets contain one of the largest stores of angiogenic and mitogenic factors and the tumor vasculature is leaky, which allows platelets to come in contact with the tumor and deposit multiple angiogenic factors including vascular endothelial growth factor (VEGF) and thrombin to tumor cells, which in turn contributes to tumor progression. This article reviews the recent literature on how platelets contribute to tumor growth, angiogenesis, and metastasis.

REFERENCES

• 1 Loreto M F, De Martinis M, Corsi M P, Modesti M, Ginaldi L. Coagulation and cancer: implications for diagnosis and management.  Pathol Oncol Res . 2000;  6 301-312
  PubMedGoogle Scholar
• 2 Hejna M, Raderer M, Zielinski C C. Inhibition of metastases by anticoagulants.  J Natl Cancer Inst . 1999;  91 22-36
  CrossrefPubMedGoogle Scholar
• 3 Tang D G, Honn K V. Adhesion molecules and tumor metastasis: an update.  Invasion Metastasis . 1994;  14 109-122
  PubMedGoogle Scholar
• 4 Steinert B W, Tang D G, Grossi I M, Umbarger L A, Honn K V. Studies on the role of platelet eicosanoid metabolism and integrin α_IIbβ₃ in tumor-cell-induced platelet aggregation.  Int J Cancer . 1993;  54 92-101
  PubMedGoogle Scholar
• 5 Timar J, Chopra H, Rong X. Calcium channel blocker treatment of tumor cells induces alterations in the cytoskeleton, mobility of the integrin α_IIbβ₃ and tumor-cell-induced platelet aggregation.  J Cancer Res Clin Oncol . 1992;  118 425-434
  CrossrefPubMedGoogle Scholar
• 6 Tang D G, Grossi I M, Tang K Q. Inhibition of TPA and 12(S)-HETE-stimulated tumor cell adhesion by prostacyclin and its stable analogs: rationale for their antimetastatic effects.  Int J Cancer . 1995;  60 418-425
  PubMedGoogle Scholar
• 7 Jordan R E, Wagner C L, Mascelli M A. Preclinical development of c7E3 Fab; a mouse/human chimeric monoclonal antibody fragment that inhibits platelet function by blockade of Gp IIb/IIIa receptors with observations on the immunogenicity of c7E3 Fab in humans. In: Horton MA, ed. Adhesion Receptors as Therapeutic Targets New York: CRC Press 1996: 281-305
  Google Scholar
• 8 Mascelli M A, Lance E T, Damaraju L. The pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GpIIb/IIIa receptor blockade.  Circulation . 1998;  97 1680-1688
  PubMedGoogle Scholar
• 9 Lincoff A M, Tcheng J E, Califf R M, for the EPILOG Investigators. Sustained suppression of ischemic complications of coronary intervention by platelet GpIIb/IIIa blockade with abciximab. One year outcome of the EPILOG trial.  Circulation . 1999;  99 1951-1958
  CrossrefPubMedGoogle Scholar
• 10 Topol E J, Ferguson J J, Weisman H F, for the EPIC Investigators. Long-term prevention from myocardial ischemic events in a randomized trial of brief integrin β₃ blockade with percutaneous coronary intervention.  JAMA . 1997;  278 479-484
  CrossrefPubMedGoogle Scholar
• 11 Felding-Habermann B, O'Toole T E, Smith J W. Integrin activation controls metastasis in human breast cancer.  Proc Natl Acad Sci USA . 2001;  98 1853-1858
  CrossrefPubMedGoogle Scholar
• 12 Nierodzik M L, Klepfish A, Karpatkin S. Role of platelets, thrombin, integrin IIb-IIIa, fibronectin and von Willebrand factor on tumor adhesion in vitro and metastasis in vivo.  Thromb Haemost . 1995;  74 282-290
  PubMedGoogle Scholar
• 13 Zucchella M, Dezza L, Pacchiarini L. Human tumor cells cultured ``in vitro'' activate platelet function by producing ADP or thrombin.  Haematologica . 1989;  74 541-545
  PubMedGoogle Scholar
• 14 Seto S-I, Onodera H, Kaido T. Tissue factor expression in human colorectal carcinoma.  Cancer . 2000;  88 295-301
  CrossrefPubMedGoogle Scholar
• 15 Ogiichi T, Yutaka H, Nakamura S. Tissue factor and cancer procoagulant expressed by glioma cells participate in their thrombin-mediated proliferation.  J Neurooncol . 2000;  46 1-9
  CrossrefPubMedGoogle Scholar
• 16 Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration.  Br J Cancer . 2000;  83 164-170
  Google Scholar
• 17 Nierodzik M L, Plotkin A, Kajumo F, Karpatkin S. Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo.  J Clin Invest . 1991;  87 229-236
  CrossrefPubMedGoogle Scholar
• 18 Nierodzik M L, Kajumo F, Karpatkin S. Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo.  Cancer Res . 1992;  52 3267-3272
  PubMedGoogle Scholar
• 19 Butenas S, Cawthern K, Veer C. Antiplatelet agents in tissue factor-induced blood coagulation.  Blood . 2001;  97 2314-2322
  CrossrefPubMedGoogle Scholar
• 20 Amirkhosravi A, Amaya M, Siddiqui F. Blockade of GpIIb/IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis.  Platelets . 1999;  10 285-292
  CrossrefPubMedGoogle Scholar
• 21 Pinedo H M, Verheul H MW, D'Amato R J, Folkman J. Involvement of platelets in tumour angiogenesis?.  Lancet . 1998;  352 1775-1777
  CrossrefPubMedGoogle Scholar
• 22 Heyn Adu P, Lötter M G, Badenhorst P N. Kinetics, distribution and site of destruction of ¹¹¹indium-labelled human platelets.  Br J Haematol . 1980;  44 269-280
  PubMedGoogle Scholar
• 23 Chronos N, Marciniak S J, Nakada M T. Binding specificity and associated effects of platelet GpIIb/IIIa inhibitors.  Eur Heart J . 1999;  1(Suppl E) E11-E17
  PubMedGoogle Scholar
• 24 Möhle R, Green D, Moore M AS, Nachman R L, Rafii S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets.  Proc Natl Acad Sci USA . 1997;  94 663-668
  CrossrefPubMedGoogle Scholar
• 25 Maloney J P, Silliman C C, Ambruso D R. In vitro release of vascular endothelial growth factor during platelet aggregation.  Am J Physiol . 1995;  275 H1054-H1061
  PubMedGoogle Scholar
• 26 Jelkman W. Pitfalls in the measurement of circulating vascular endothelial growth factor.  Clin Chem . 2001;  47 617-623
  PubMedGoogle Scholar
• 27 Verheul H MW, Jorna A S, Hoekman K. Vascular endothelial growth factor-stimulated endothelial cells promote adhesion and activation of platelets.  Blood . 2000;  96 4216-4221
  PubMedGoogle Scholar
• 28 Trikha M, Zhou Z, Jordan R, Nakada M T. ReoPro and m7E3 F(ab′)₂ inhibit β3 integrin mediated tumor growth and angiogenesis.  Proc Am Assoc Cancer Res . 2000;  42 824-824 Abst 3678
  PubMedGoogle Scholar
• 29 Cox G, Walker R A, Andi A, Steward W P, O'Byrne K J. Prognostic significance of platelet and microvessel counts in operable non-small cell lung cancer.  Lung Cancer . 2000;  29 169-177
  PubMedGoogle Scholar
• 30 Pedersen L M, Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer.  Eur Respir J . 1996;  9 1826-1830
  CrossrefPubMedGoogle Scholar
• 31 Gücer F, Moser F, Tamussino K. Thrombocytosis as a prognostic factor in endometrial carcinoma.  Gynecol Oncol . 1998;  70 210-214
  CrossrefPubMedGoogle Scholar
• 32 Salgado R, Vermeulen P B, Benoy I. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels in advanced cancer patients.  Br J Cancer . 1999;  80 892-897
  CrossrefPubMedGoogle Scholar
• 33 Browder T, Folkman J, Pirie-Shepherd S. The hemostatic system as a regulator of angiogenesis.  J Biol Chem . 2000;  275 1521-1524
  CrossrefPubMedGoogle Scholar
• 34 Nieswandt B, Hafner M, Echtendacher B, Mannel D N. Lysis of tumor cells by natural killer cells in mice is impeded by platelets.  Cancer Res . 1999;  59 1295-1300
  PubMedGoogle Scholar
• 35 Borsig L, Wong R, Feramisco J. Heparin and cancer revisited. Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis.  Proc Natl Acad Sci USA . 2001;  98 3352-3357
  CrossrefPubMedGoogle Scholar
• 36 Belloc C, Lu H, Soria C. The effect of platelets on invasiveness and protease production of human mammary tumor cells.  Int J Cancer . 1995;  60 413-417
  PubMedGoogle Scholar
• 37 Cohen S A, Trikha M, Mascelli M A. Potential future clinical applications for the GpIIb/IIIa antagonist, abciximab in thrombosis, vascular and oncological indications.  Pathol Oncol Res . 2000;  6 163-174
  PubMedGoogle Scholar
• 38 Coller B S. Anti-GpIIb/IIIa drugs: current strategies and future directions.  Thromb Haemost . 2001;  86 427-443
  PubMedGoogle Scholar
• 39 Klement G, Baruchel S, Rak J. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induce tumor regression without overt toxicity.  J Clin Invest . 2000;  105 1045-1047
  PubMedGoogle Scholar
• 40 Folkman J, Browder T, Palmblad J. Angiogenesis research: guidelines for translation to clinical application.  Thromb Haemost . 2001;  86 23-33
  PubMedGoogle Scholar