Ans. is 'a' i.e., Angiogenesis * Tumour angiogenesis plays a very significant role in the metastasis since the new vessel formed as a part 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 tumoursTumour 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 1- 2 mm zone represents the maximal distance across which oxygen and nutrients can diffuse from blood vessels.Angiogenesis of tumour imparts two benefitsGrowth of tumourBy supplying oxygen and nutrient to tumour cells.Endothelial cells of new blood vessels secrete growth factors which stimulate the growth of adjacent tumour cells.Distant metastasisWithout access to the vasculature, the tumour cells cannot rapidly spread to distant sites.Tumour associated angiogenic factors * Tumours secrete certain factors which induce neovascularizationTwo most important are -Vascular endothelial derived growth factor (VEGF)Basic fibroblast growth factor (BFGF)Steps in the spread of cancer -Aggressive clonal proliferation and angiogenesisThe first step in the spread of cancer cells is the development of rapidly proliferating clone of cancer cells. Detachment of tumour cellsNormal 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 interactionLoosened cancer cells attach to ECM proteins mainly Laminin and fibronectin through a special protein integrin.Degradation of ECMTumour cells overexpress proteases and matrix degrading enzymes i.e., metalloproteinases that includes collagenase and gelatinase.Another protease cathepsin D is also increased in certain 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.Autocrine motility factor (AMF) is a cytokine derived from tumour cells and stimulate receptor mediated motility of tumour cells.Cleavage product of matrix components. Which are formed following degradation of ECM have properties of tumour cell chemotaxis, 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 cellsTumour 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.