Molecular basics of tumor angiogenesis. Key players of tumor angiogenesis and their main functions are depicted here. (a) Once a tumor has reached a volume of 1-2 mm3, tumor cells start to be hypoxic, and HIF1α is stabilized. Activated HIF pathway leads to the expression of several genes (within green square) which greatly contribute to VEGF production. VEGF amplify this system through VEGF-dependent MMPs expression involved in ECM degradation and growth factors release. VEGF acts as a chemoattractant on endothelial cells from the nearest vessels and triggers vessel sprouting. Stimulated VEGFR2 leads to the expression of Dll4, a Notch ligand which inhibits the tip cell transformation through VEGFR1 upregulation. VEGFR activation mediates proteases expression, VE-Cad complex disruption leading to cell/cell and cell/matrix detachment. In parallel, Tie2 stimulation by Ang2 induces pericytes detachment. This step is required for endothelial cell migration and proliferation. (b) While tip cells drive vessel elongation towards the source of VEGF and through EphB4/ephrinB2 signaling, tumor cells attract stromal cells. These stromal cells, comprising tumor-associated macrophages (TAM) and fibroblasts contribute to tumor angiogenesis through secretion of proangiogenic factors. During vessel elongation, new ECM is synthesized, and few pericytes will cover the neovessel. This—in conjunction with NO production and disruption of adherens junctions—results in a leaky vessel. (c) The resulting vasculature is tortuous with many dead ends and is prone to cell extravasation. Moreover, endothelial cells contribute to tumor growth by secreting supporting molecules in addition to carrying nutrients and oxygen.
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