Principles of Cancer Biology Chapter 3 notes read before lecture 6 Angiogenesis A term that refers to the proves by which new blood vessels sprout and grow from pre existing vessels in the surrounding normal tissues Angiogenesis is a normal biological event that occurs at specific times for specific purposes Example An embryo in the womb must create the vast network of arteries veins and capillaries that are needed for a mature circulatory system The embryo first creates a primary population of cells called endothelial cells that form the inner lining of blood vessels Vasculogenesis The newly created endothelial cells are organized into a primitive network of channels representing the major blood vessels of the circulatory system Angiogenesis involves an extensive phase of growth and proliferation of pre existing endothelial cells which form buds that sprout from existing vessels and develop into an interconnected network of new vessels Angiogenesis continues to occur after birth when additional blood vessels are required Angiogenesis is therefore activated a few days each month in the uterine lining of women of reproductive age In both male and female angiogenesis is also called upon anytime an injury requires new blood vessels for wound healing and tissue repair Angiogenesis needs to be precisely regulated in such cases It was suggested that tumors release signaling molecules that trigger the growth of new blood vessels in the surrounding host tissues And that these new blood vessels are required to sustain tumor growth Virtually every tumor stopped growing at exactly the same size suggesting that some kind of limitation allowed them to grow only so far This process by which cancer cells stimulate the development of a blood supply is called tumor angiogenesis Two of the proteins vascular endothelial growth factor VEGF and Fibroblast growth factor FGF appear to be specifically important for sustaining tumor growth They trigger angiogenesis by bending to specific receptor proteins located on the surface of endothelial cells VEGF molecules encounter an endothelial cell they bind to and activate VEGF receptors located on the endothelial cell surface As a result endothelial cells begin to proliferate and produce matrix metalloproteinsases MMPs The MMPs break down components of the extracellular matrix that fills the spaces between neighboring cells Thereby allowing the endothelial cells to migrate into the surrounding tissues As they migrate the proliferating endothelial cells become organized into hollow tubes that evolve into new networks of blood vessels For angiogenesis to proceed these molecules must overcome the effects of angiogenesis inhibitors that normally restrain the growth of blood vessels More than a dozen naturally occurring inhibitors of angiogenesis have been identified Including the proteins angiostatin endostatin and thrombospondin A finely tuned balance between the concentration of these angiogenesis inhibitors and the concentration of activators such as VEGF and FGF determines whether a tumor will induce the growth of new blood vessels Using angiogenesis inhibitors to block vessel formation might be useful for slowing tumor growth In a study mice were injected with the inhibitors after a few cycles of treatment the primary tumors virtually disappeared Angiogenesis inhibitors drugs might be useful in preventing metastasis Angiogenesis inhibiors did reduce the rate of metastasis 18 fold Tumor dormancy In which cancer cells spread from a primary tumor to another organ and form tiny clumps of cancer cells that remain dormant for prolonged periods of time This may be caused by micrometastasis wehre they may not need angiogenesis to survive Invasion Refers to the direct migration and penetration of cancer cells into neighboring tissues whereas metastasis involves the ability of cancer cells to enter the blood stream First cancer cells invade surrounding tissues and penetrate through the walls of lymphatic and blood vessels thereby gaining access to the bloodstream Second these cancer cells are then transported by the circulatory system throughout the body And third the cancer cells leave the bloodstream and enter particular organs where they establish new metastic tumors In most tissues adjoining cells are held together by binding interactions between cell cell adhesion proteins found on the outer surface of each cell These molecules are often missing or deficient in cancer cells thereby allowing cells to separate from the main tumor mass more readily E cadherin A cell cell adhesion protein that normally binds epithelial cells to one another Cell Mortality When activated after the loss of cell cell adhesion permits cancer cells to detach from one another Proteases The purpose of these enzymes is to break down structures that would otherwise represent barriers to cancer cell movement Human cancers are separated from underlying tissues by a thin dense layer of protein containing material called the basal lamina Cancer cells break through this barrier by producing protease that facilitate degradation of the proteins that form the backbone of the basal lamina Apparently the bloodstream is an inhospital place for most cancer cells and only a tiny number survive the trip to potential sites of metastasis Such cell populations each derived from the proliferation of a single initial cell are referred to as clones Cells in a primary tumor differ in their ability to metastasize Cancer arising in each organ preferentially metastasize to particular locations Ex Stomach and colon cancers frequently metastasize to the liver prostate and breast cancers often metastasize to bone and many forms of cancer tend to metastasize to the lungs The most probable site for circulating cancer cells to become stuck is in capillaries the tiny vessels whose diameter is generally is generally no longer than that of a single blood cell Cancer cells often become lodged in tiny capillaries The cancer cells may then adhere and penetrate through the capillary walls and invade the surrounding organ beginning the formation of a new metastic tumor Metastic tumors may therefore end up growing and invading more efficiently than the original primary tumor shedding more cells into the blood stream and generating further metastases that are even more aggressive This gradual change in the properties of a tumor cell population as cells acquire more and more aberrant traits and become increasingly aggressive is
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