TAILIEUCHUNG - 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. | 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 are physiologic. B. Tumors have abnormal vessels with tortuous branching and dilated irregular interconnecting branches causing uneven blood flow with areas of hypoxia and acidosis. This harsh environment selects genetic events that result in resistant tumor variants such as the loss of p53. High levels of VEGF secreted by tumor cells disrupt gap junction communication tight junctions and adherens junctions between EC via src-mediated phosphorylation of proteins such as connexin 43 zonula occludens-1 VE-cadherin and a 0-catenins. Tumor vessels have thin irregular BM and pericytes are sparse or absent. Together these molecular abnormalities result in a vasculature that is permeable to serum macromolecules leading to high tumor interstitial pressure which can prevent the delivery of drug s to the tumor cells. This is made worse by the binding and activation of platelets at sites of exposed BM with release of stored VEGF and microvessel clot formation creating more abnormal blood flow and regions of hypoxia. C. In experimental systems treatment with bevacizumab or blocking antibodies to VEGFR2 leads to changes in the tumor vasculature that has been termed vessel normalization. During the first week of treatment abnormal vessels are eliminated or pruned dotted lines .

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