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....
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 15) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 15) Tumor angiogenesis is a complex process involving many different celltypes that must proliferate, migrate, invade, and differentiate in response to signalsfrom the tumor microenvironment. Endothelial cells (ECs) sprout from hostvessels in response to VEGF, bFGF, Ang2, and other proangiogenic stimuli.Sprouting is stimulated by VEGF/VEGFR2, Ang2/Tie-2, and integrin/extracellularmatrix (ECM) interactions. Bone marrow–derived circulating endothelialprecursors (CEPs) migrate to the tumor in response to VEGF and differentiate intoECs, while hematopoietic stem cells differentiate into leukocytes, includingtumor-associated macrophages that secrete angiogenic growth factors and produceMMPs that remodel the ECM and release bound growth factors. Tumor cellsthemselves may directly form parts of vascular channels within tumors. Thepattern of vessel formation is haphazard: vessels are tortuous, dilated, leaky, andbranch in random ways. This leads to uneven blood flow within the tumor, withareas of acidosis and hypoxia (which stimulate release of angiogenic factors) andhigh intratumoral pressures that inhibit delivery of therapeutic agents. Figure 80-9 Critical molecular determinants of endothelial cell biology. Angiogenicendothelium expresses a number of receptors not found on resting endothelium.These include receptor tyrosine kinases (RTK) and integrins that bind to theextracellular matrix and mediate endothelial cells adhesion, migration, andinvasion. Endothelial cells (ECs) also express RTK (i.e., the FGF and PDGFreceptors) that are found on many other cell types. Critical functions mediated byactivated RTK include proliferation, migration, and enhanced survival ofendothelial cells, as well as regulation of the recruitment of perivascular cells andbloodborne circulating endothelial precursors and hematopoietic stem cells to thetumor. Intracellular signaling via EC-specific RTK utilizes molecular pathwaysthat may be targets for future antiangiogenic therapies. Figure 80-10