Chapter 080. Cancer Cell Biology and Angiogenesis (Part 17)

VEGF and its receptors are required for vasculogenesis (the de novo formation of blood vessels from differentiating endothelial cells, as occurs during embryonic development) and angiogenesis under normal (wound healing, corpus luteum formation) and pathologic processes (tumor angiogenesis, inflammatory conditions such as rheumatoid arthritis). VEGF-A is a heparin-binding glycoprotein with at least four isoforms (splice variants) that regulates blood vessel formation by binding to the RTKs VEGFR1 and VEGFR2, which are expressed on all ECs in addition to a subset of hematopoietic cells (Fig. 80-8). VEGFR2 regulates EC proliferation, migration, and survival, while VEGFR1 may act as an antagonist...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 17) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 17) VEGF and its receptors are required for vasculogenesis (the de novoformation of blood vessels from differentiating endothelial cells, as occurs duringembryonic development) and angiogenesis under normal (wound healing, corpusluteum formation) and pathologic processes (tumor angiogenesis, inflammatoryconditions such as rheumatoid arthritis). VEGF-A is a heparin-bindingglycoprotein with at least four isoforms (splice variants) that regulates bloodvessel formation by binding to the RTKs VEGFR1 and VEGFR2, which areexpressed on all ECs in addition to a subset of hematopoietic cells (Fig. 80-8).VEGFR2 regulates EC proliferation, migration, and survival, while VEGFR1 mayact as an antagonist of R1 in ECs but is probably also important for angioblastdifferentiation during embryogenesis. Tumor vessels appear to be more dependenton VEGFR signaling for growth and survival than normal ECs. While VEGFsignaling is a critical initiator of angiogenesis, this is a complex process regulatedby additional signaling pathways (Fig. 80-9). The angiopoietin, Ang1, producedby stromal cells, binds to the EC RTK Tie-2 and promotes the interaction of ECswith the ECM and perivascular cells, such as pericytes and smooth-muscle cells,to form tight, non-leaky vessels. PDGF and basic fibroblast growth factor (bFGF)help to recruit these perivascular cells. Ang1 is required for maintaining thequiescence and stability of mature blood vessels and prevents the vascularpermeability normally induced by VEGF and inflammatory cytokines. For tumor cell–derived VEGF to initiate sprouting from host vessels, thestability conferred by the Ang1/Tie2 pathway must be perturbed; this occurs bythe secretion of Ang2 by ECs that are undergoing active remodeling. Ang2 bindsto Tie2 and is a competitive inhibitor of Ang1 action: under the influence of Ang2,preexisting blood vessels become more responsive to remodeling signals, with lessadherence of ECs to stroma and associated perivascular cells and moreresponsiveness to VEGF. Therefore, Ang2 is required at early stages of tumorangiogenesis for destabilizing the vasculature by making host ECs more sensitiveto angiogenic signals. Since tumor ECs are blocked by Ang2, there is nostabilization by the Ang1/Tie2 interaction, and tumor blood vessels are leaky,hemorrhagic, and have poor association of ECs with underlying stroma. Sproutingtumor ECs express high levels of the transmembrane protein ephrin-B2 and itsreceptor, the RTK EPH whose signaling appears to work with the angiopoietinsduring vessel remodeling. During embryogenesis, EPH receptors are expressed onthe endothelium of primordial venous vessels while the transmembrane ligandephrin-B2 is expressed by cells of primordial arteries; the reciprocal expressionmay regulate differentiation and patterning of the vasculature. A number of ubiquitously expressed host molecules play critical roles innormal and pathologic angiogenesis. Proangiogenic cytokines, chemokines, andgrowth factors secreted by stromal cells or inflammatory cells make importantcontributions to neovascularization, including bFGF, transforming growth factor-α(TGF-α), TNF-α, and IL-8. In contrast to normal endothelium, angiogenicendothelium overexpresses specific members of the integrin family of ECM-binding proteins that mediate EC adhesion, migration, and survival. Specifically,expression of integrins αvβ3, αvβ5, and α5β1 mediate spreading and migration ofECs and are required for angiogenesis induced by VEGF and bFGF, which in turncan upregulate EC integrin expression. The α vβ3 integrin physically associateswith VEGFR2 in the plasma membrane and promotes signal transduction fromeach receptor to promote EC proliferation (via focal adhesion kinase, src, PI3K,and other pathways) and survival (by inhibition of p53 and increasing the Bcl-2/Bax expression ratio). In addition, α vβ3 forms cell surface complexes with matrixmetalloproteinases (MMPs), zinc-requiring proteases that cleave ECM proteins,leading to enhanced EC migration and the release of heparin-binding growthfactors including VEGF and bFGF. EC adhesion molecules can be upregulated(i.e., by VEGF, TNF-α) or downregulated (by TGF-β); this, together with chaoticblood flow explains poor leukocyte-endothelial interactions in tumor blood vesselsand may help tumor cells avoid immune surveillance. Cells derived from hematopoietic progenitors in the host bone marrowcontribute to tumor angiogenesis in a process linked to the secretion of VEGF andPlGF (placenta-derived growth factor) by tumor cells and their surroundingstroma. VEGF promotes the mobilization and recruitment of circulating ...