Platelet Endothelial Interaction in Tumor Angiogenesis

1,2Philipp C. Manegold and 1,3Marc Dellian institute for Surgical Research, Klinikum Grosshadern, University of Munich, Germany 2Department of Surgery, Klinikum Grosshadern, University of Munich, Germany 3Department of Otorhinolaryngology, Head and Neck Surgery, Klinikum Grosshadern, University of Munich, Germany

Tumor angiogenesis, the growth of new blood vessels from preexisting blood vessels, is indispensable for tumor growth and tumor metastasis. Activated blood coagulation has been linked to tumor angiogenesis since clotting factors were found to promote endothelial cell proliferation. Beside plasmatic clotting factors, platelets may be involved in angiogenic processes: they release pro- and anti-angiogenic growth factors upon activation and aggregation and promote formation of capillary-like structures in vitro [1, 2].

Tumor angiogenesis is a complex process regulated by a versatile number of mediators [3]. Focusing on general mechanisms, tumor angiogenesis is induced by endothe-lium-specific growth factors VEGF and FGF, but also by cytokines (TNF, IL-1) and clotting factors that are released from tumor cells as well as from macrophages and fibroblasts. On preexisting venules growth factors and cytokines stimulate endothelial cells and induce loosening of intercellular junctions of endothelial cells (PECAM, VE-cadherin) and smooth muscle cells. Therefore, angiogenic endothe-lium is highly permeable, leading to extravasation of plasma proteins such as fibrinogen and clotting factors. Extravascu-lar fibrin meshes provide a provisional tumor matrix. Proteases, especially urokinase plasminogen activator (uPA) and matrix metalloproteinases (MMPs, e.g., progelatinase A) expressed on proliferating endothelial cells, facilitate sprouting of blood vessels into the fibrin matrix toward the stimuli.

The established tumor microcirculation is characterized by its high vascular density, chaotic vascular branching, and aneurysmatic sacculations. High vascular permeability is a consequence of sustained influence of growth factors and cytokines and is a result of intercellular gaps in tumor microvessels. Mosaic blood vessels composed of endothelial cells and nonendothelial cells forming vascular lumen are frequently found [4]. High vascular resistance and high blood viscosity result in sluggish blood flow within the tumor microcirculation. Anoxic, acidotic areas within the tumor center appear in consequence of redistribution of blood perfusion to peripheral areas [5].

Therefore, tumor angiogenesis might provide a pro-thrombotic environment that favors interactions of platelets with the angiogenic endothelium. Platelet-endothelial interactions might affect tumor angiogenesis by release of angiogenic growth factors from activated platelets. Spontaneous thrombosis, however, might result in tumor necrosis.

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