Tumor angiogenesis. Tumor angiogenesis is a multistep process that occurs in almost all tumors and that is mediated by endothelial cells (ECs). When a cell has acquired genetic alterations that allow unlimited growth and escape from apoptosis, a small tumor is formed (A). As soon as the tumor volume has reached a few cubic millimeters, oxygen and nutrient supply are insufficient, and the tumor cells undergo an angiogenesis switch. This results in the production and release of growth factors into the surrounding tissue. The secreted growth factors bind to receptors on ECs in nearby vessels. Pericytes that stabilize the vessel detach, and vessel dilation occurs (B). In addition, the activated ECs start to produce proteases (not shown) that degrade the basal membrane and the extracellular matrix (C). Subsequently, the ECs start to migrate (D) and proliferate (E) into the growth factor gradient, forming new vascular structures. Finally, matrix proteins are deposited, and the new vessel is stabilized by pericytes to form a functional and mature blood vessel. The tumor cells can continue to grow, and metastasis formation is facilitated since the tumor cells now have easy access to the circulation (F).