Chapter 080. Cancer Cell Biology and Angiogenesis (Part 15) Tumor angiogenesis is a complex process involving many different cell types that must proliferate, migrate, invade, and differentiate in response to signals from the tumor microenvironment. Endothelial cells (ECs) sprout from host vessels in response to VEGF, bFGF, Ang2, and other proangiogenic stimuli. Sprouting is stimulated by VEGF/VEGFR2, Ang2/Tie-2, and integrin/extracellular matrix (ECM) interactions. Bone marrow–derived circulating endothelial precursors (CEPs) migrate to the tumor in response to VEGF and differentiate into ECs, while hematopoietic stem cells differentiate into leukocytes, including tumor-associated macrophages that secrete angiogenic growth factors and produce MMPs that remodel the ECM and release bound growth factors. Tumor cells themselves may directly form parts of vascular channels within tumors. The pattern of vessel formation is haphazard: vessels are tortuous, dilated, leaky, and branch in random ways. This leads to uneven blood flow within the tumor, with areas of acidosis and hypoxia (which stimulate release of angiogenic factors) and high intratumoral pressures that inhibit delivery of therapeutic agents. Figure 80-9 Critical molecular determinants of endothelial cell biology. Angiogenic endothelium expresses a number of receptors not found on resting endothelium. These include receptor tyrosine kinases (RTK) and integri ns that bind to the extracellular matrix and mediate endothelial cells adhesion, migration, and invasion. Endothelial cells (ECs) also express RTK (i.e., the FGF and PDGF receptors) that are found on many other cell types. Critical functions mediated by ac tivated RTK include proliferation, migration, and enhanced survival of endothelial cells, as well as regulation of the recruitment of perivascular cells and bloodborne circulating endothelial precursors and hematopoietic stem cells to the tumor. Intracellular signaling via EC- specific RTK utilizes molecular pathways that may be targets for future antiangiogenic therapies. Figure 80-10 . Chapter 080. Cancer Cell Biology and Angiogenesis (Part 15) Tumor angiogenesis is a complex process involving many different cell types that must proliferate, migrate, invade, and differentiate. extracellular matrix and mediate endothelial cells adhesion, migration, and invasion. Endothelial cells (ECs) also express RTK (i.e., the FGF and PDGF receptors) that are found on many other cell types migration, and enhanced survival of endothelial cells, as well as regulation of the recruitment of perivascular cells and bloodborne circulating endothelial precursors and hematopoietic stem cells