Chapter 080. Cancer Cell Biology and Angiogenesis (Part 16)

Normalization of tumor blood vessels due to inhibition of VEGF signaling.A. Blood vessels in normal tissues exhibit a regular hierarchical branching pattern that delivers blood to tissues in a spatially and temporally efficient manner to meet the metabolic needs of the tissue (top). At the microscopic level, tight junctions are maintained between endothelial cells (EC), which are adherent to a thick and evenly distributed basement membrane (BM). Pericytes form a surrounding layer that provides trophic signals to the EC and helps maintain proper vessel tone. Vascular permeability is regulated, interstitial fluid pressure is low, and oxygen tension and pH...
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Chapter 080. Cancer Cell Biology and Angiogenesis (Part 16) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 16) Normalization of tumor blood vessels due to inhibition of VEGFsignaling. A. Blood vessels in normal tissues exhibit a regular hierarchical branchingpattern that delivers blood to tissues in a spatially and temporally efficient mannerto meet the metabolic needs of the tissue (top). At the microscopic level, tightjunctions are maintained between endothelial cells (EC), which are adherent to athick and evenly distributed basement membrane (BM). Pericytes form asurrounding layer that provides trophic signals to the EC and helps maintainproper vessel tone. Vascular permeability is regulated, interstitial fluid pressure islow, and oxygen tension and pH are physiologic. B. Tumors have abnormalvessels with tortuous branching and dilated, irregular interconnecting branches,causing uneven blood flow with areas of hypoxia and acidosis. This harshenvironment selects genetic events that result in resistant tumor variants, such asthe loss of p53. High levels of VEGF (secreted by tumor cells) disrupt gapjunction communication, tight junctions, and adherens junctions between EC viasrc-mediated phosphorylation of proteins such as connexin 43, zonula occludens-1, VE-cadherin, and α/β-catenins. Tumor vessels have thin, irregular BM, andpericytes are sparse or absent. Together, these molecular abnormalities result in avasculature that is permeable to serum macromolecules, leading to high tumorinterstitial pressure, which can prevent the delivery of drugs to the tumor cells.This is made worse by the binding and activation of platelets at sites of exposedBM, with release of stored VEGF and microvessel clot formation, creating moreabnormal blood flow and regions of hypoxia. C. In experimental systems,treatment with bevacizumab or blocking antibodies to VEGFR2 leads to changesin the tumor vasculature that has been termed vessel normalization. During thefirst week of treatment, abnormal vessels are eliminated or pruned (dotted lines),leaving a more normal branching pattern. ECs partially regain features such ascell-cell junctions, adherence to a more normal BM, and pericyte coverage. Thesechanges lead to a decrease in vascular permeability, reduced interstitial pressure,and a transient increase in blood flow within the tumor. Note that in murinemodels, this normalization period lasts only for ~5–6 days. D. After continuedanti-VEGF/VEGFR therapy (which is often combined with chemo- orradiotherapy), ECs die, leading to tumor cell death (either due to direct effects ofthe chemotherapy or lack of blood flow). Unlike normal blood vessels, the vascular lining of tumor vessels is not ahomogeneous layer of ECs but often consists of a mosaic of ECs and tumor cells;the concept of cancer cell–derived vascular channels, which may be lined by ECMsecreted by the tumor cells, is referred to as vascular mimickry. It is unclearwhether tumor cells actually form structural elements of vascular channels orrepresent tumor cells in transit into or out of the vessel. However, the former issupported by evidence that in some human colon cancers, tumor cells cancomprise up to 15% of vessel walls. The ECs of angiogenic blood vessels areunlike quiescent ECs found in adult vessels, where only 0.01% of ECs aredividing. During tumor angiogenesis, ECs are highly proliferative and express anumber of plasma membrane proteins that are characteristic of activatedendothelium, including growth factor receptors and adhesion molecules such asintegrins. Mechanisms of Tumor Vessel Formation Tumors utilize a number of mechanisms to promote their vascularization,and in each case they subvert normal angiogenic processes to suit this purpose(Fig. 80-8). Primary or metastatic tumor cells sometimes arise in proximity to hostblood vessels and grow around these vessels, parasitizing nutrients by coopting thelocal blood supply. However, most tumor blood vessels arise by the process ofsprouting, in which tumors secrete trophic angiogenic molecules, the most potentbeing VEGF, that induce the proliferation and migration of host ECs into thetumor. Sprouting in normal and pathogenic angiogenesis is regulated by threefamilies of transmembrane RTKs expressed on ECs and their ligands (VEGFs,angiopoietins, ephrins; Fig. 80-9), which are produced by tumor cells,inflammatory cells, or stromal cells in the tumor microenvironment. When tumor cells arise in or metastasize to an avascular area, they grow toa size limited by hypoxia and nutrient deprivation. Hypoxia, a key regulator oftumor angiogenesis, causes the transcriptional induction of the gene encodingVEGF by a process that involves stabilization ...