Angiogenesis Tumour angiogenesis plays a very significant role in the metastasis since the new vessel formed as a pa of growing tumour are more vulnerable to invasion because these evolving cells are in direct contact with cancer cells. According to Harrison "Cancer research studying the conditions necessary for cancer metastasis have discovered that one of the critical events required is the, growth of a new network of blood vessels called tumour angiogenesis". Angiogenesis in tumours :? Tumour stimulates the growth of host blood vessels. Which is essential for supplying nutrients to the tumour. Tumours cannot enlarge beyond 1-2 mm in diameter or thickness unless they are vascularized because the 12 mm zone represents the maximal distance across which oxygen and nutrients can diffuse from blood vessels. Angiogenesis of tumour impas two benefits A) Growth of tumour By supplying oxygen and nutrient to tumour cells. Endothelial cells of new blood vessels secrete growth factors which stimulate the growth of adjacent tumour cells. B) Distant metastasis Without access to the vasculature, the tumour cells cannot rapidly spread to distant sites. Tumour associated angiogenic factors :? Tumours secrete ceain factors which induce neovascularization Two most impoant are ? i) Vascular endothelial derived growth factor (VEGF) ii) Basic fibroblast growth factor (BFGF) Steps in the spread of cancer ? Aggressive clonal proliferation and angiogenesis The first step in the spread of cancer cells is the development of rapidly proliferating clone of cancer cells. Detachment of tumour cells Normal cells remain glued to each other due to presence of cell adhesion molecules (CAM) i.e. E cadherin. Normal function of E cadherin is dependent on catenins that helps in linkage of cytoskeleton to E cadherin. Down regulation of expression of either E cadherins or catenins results in loosening of cells that helps in metastasis. Tumour cell and extracellular matrix interaction Loosened cancer cells attach to ECM proteins mainly Laminin and fibronectin through a special protein integrin. Degradation of ECM Tumour cells overexpress proteases and matrix degrading enzymes i.e., metalloproteinases that includes collagenase and gelatinase. Another protease cathepsin D is also increased in ceain cancers. These enzymes bring about dissolution of extracellular matrix - Firstly basement membrane of tumour itself; is dissolved then it make way for the tumour cells through the interstitial matrix and.finally the basement membrane of the vessel wall is dissolved. Entry of tumour cells into capillary lumen :? Tumour cells after degrading the basement membrane are ready to migrate into lumen of capillaries or venules for which the following mechanisms play a role. i) Autocrine motility factor (AMF) is a cytokine derived from tumour cells and stimulate receptor mediated motility of tumour cells. ii) Cleavage product of matrix components. Which are formed following degradation of ECM have propeies of tumour cell chemotcuis, growth promotion and angiogenesis in cancer. After the malignant cells have migrated through the breached basement membrane, these cells enter the lumen of lymphatic and capillary channels. Thrombus formation The tumour cells protruding in the lumen of the capillary are now covered with constituents of the circulating blood and form the thrombus. Thrombus provides nourishment to the tumour cells and also prevent them from immune attack. Extravasation of tumour cells Tumour cells in the circulation may mechanically block these vascular channels and attach to vascular end. In this way, the sequence similar to local invasion is repeated and the basement membrane is exposed.