Inhibition of Platelet Function: Does It Offer a Chance of Better Cancer Progression Control?

Abstract

Thrombocytosis is frequently (10 to 57%) observed in cancer patients. Although the mechanisms underlying thrombocytosis are not yet fully elucidated, tumor-derived factors with thrombopoietin-like activity, growth factors, platelet-derived microparticles, and factors released from bone marrow endothelial cells as well as growth factors secreted by megakaryocytes (acting via an autocrine loop) are claimed to influence this process. The course of cancer is strongly associated with hypercoagulable state, which results from direct influences of tumor cells themselves and various indirect mechanisms. Activated platelets provide procoagulant surface amplifying the coagulation process. It is well documented that proteins of the hemostatic system influence different steps of metastasis, angiogenesis, and proteolytic events. Much less is known about the role of platelets in tumor growth and their possible contribution to prevention of tumor cells from the host immune system. Multidirectional activities of platelets during tumor development and metastatic dissemination create a possibility of introducing antiplatelet agents in anticancer therapy. The spectrum of plausible therapies includes antibodies against glycoprotein IIb-IIIa, direct thrombin inhibitors, protease activated receptor-1 targeted therapy, as well as cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors. However, there is no sufficient information on a specific type of cancer where progression does depend on platelet function. Despite numerous experimental studies conducted, to date none of the new specific antiplatelet agents were tested in clinical trials in a cancer patient population.

Semaphorin signaling in cancer cells and in cells of the tumor microenvironment – two sides of a coin

“…Notably, an increasing amount of evidence suggests that platelets play important roles in tumor angiogenesis; they are a rich source both of proangiogenic factors and of inhibitors of angiogenesis, and, by adhering to the endothelium, they can also facilitate the transmigration of pro-angiogenic cells to the extracellular space (Sierko and Wojtukiewicz, 2007). Furthermore, platelets tend to aggregate with circulating tumor cells, thereby facilitating immune evasion and the binding of tumor cells to microvascular endothelium (followed by extravasation and metastasis) (Borsig, 2008).…”

The role of platelet activation in tumor metastasis

“…Based on the understanding of platelet-tumor cell aggregate formation, potential inhibitors of cancer progression are being explored [reviewed in [10,12]. Platelets adhesion molecules are involved in mediation of platelet-tumor cell interactions.…”

“…3,[8][9][10][11]. Any interference in platelet-tumor cell interactions with anti-platelet agents has consistently demonstrated potent anti-metastatic effects [reviewed in 10,12]. In this article, the mechanisms of platelet contribution to metastasis are reviewed and possible perspectives for therapeutic application are discussed.…”

A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment

“…[8][9][10][11] Subsequent animal models in which specific platelet functions were altered through drug treatment or controlled genetic ablation have led to a model of platelet-supported tumor metastasis in which tumor cells enter the bloodstream (intravasation), and bind and activate platelets (cohesion) and leukocytes. 12,13 These host cells then assist tumor cell arrest at the vessel wall (adhesion) and survival within the vasculature (immune evasion), which enables exit from the circulation (extravasation), and tumor cell survival and proliferation within target tissues of metastasis. [14][15][16] These contributions of platelets to tumor cell survival and spread suggest that agents directed against these processes may give rise to new therapies for patients with a high risk of metastasis or for minimizing the risk of cancer cell dissemination during tumor surgery.…”