Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis

Abstract

Angiogenesis formation of new capillary blood vessels is essential during development and physiological conditions, such as wound healing and the reproductive cycle. Prolonged and excessive angiogenesis has been implicated in a number of pathological processes, for instance rheumatoid arthritis, retinopathy and tumor growth. The normal vasculature is tightly regulated by a balance between proand anti-angiogenic factors. The most well studied pro-angiogenic factor vascular endothelial growth factor-A(VEGF-A) – is required for development of a vascular system during embryogenesis and is also a central regulator of adult neovascularization (Olsson et al., 2006). Angiogenesis is a multistep process involving oxygen sensing, growth factor signaling, matrix degradation, endothelial cell proliferation, migration and differentiation into a functional blood vessel. This process formation of new blood vessels from pre-existing ones must take place without compromising blood flow. Platelets are central players in maintaining hemostasis of the blood. At sites of blood vessel injury, platelets are activated to induce blood coagulation and form aggregates at the site of the damaged endothelium to prevent hemorrhage and thereby protects us from fatal bleedings. Besides their role in hemostasis, platelets have been shown to contribute to nonhemostatic processes such as wound healing, immunity, angiogenesis, cardiovascular disease and tumor metastasis (Felding-Habermann et al., 1996; Jurk and Kehrel, 2005). A connection between platelets and malignant disease has been recognized since the end of the 19th century, when Armand Trousseau observed increased thrombotic events in patients that were later diagnosed with cancer (Trousseau, 1865). This enhanced tendency to form blood clots, or hypercoagulability, is named Trousseau’s syndrome (Varki, 2007) and is especially pronounced in certain forms of cancer such as pancreatic and lung cancer. Growth of solid tumors, like all expanding tissues, is dependent on angiogenesis for oxygen and nutrient supply, as well as for removal of waste products. The hypotheses that platelets contribute to tumor-induced angiogenesis was put forward by Pinedo and collegues in 1998 (Pinedo et al., 1998). During the last decade, this hypotheses has been experimentally supported by several independent research groups, demonstrating that platelets can regulate endothelial cell behavior and angiogenesis. Platelets are now recognized as the major source of VEGF-A in the body (Holmes et al., 2008; Peterson et al., 2010; Verheul et al., 1997). In addition to stimulation of tumor growth and angiogenesis, platelets have also been found to regulate metastasis. Possible explanations involve protection of the tumor cells