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STEM CELLS, ANGIOGENESIS AND NEUROGENESIS IN TUMORS

Neovascularization, the formation of blood vessels in embryonic and established tissues, plays important roles in development, inflammation, and wound repair. All cells require oxygen and nutrients for survival and are therefore located within the diffusion limit of oxygen of blood vessels or air. New blood vessels arise during embryogenesis by the differentiation of mesenchymal cells into endothelial cells and by the coalescence of these cells in structures with intact lumens. In older embryos and adult animals, blood vessels also arise from preexisting vessels by activation, proliferation, and migration of endothelial cells through a process named “angiogenesis”. This process is characterized by sprouting of new capillaries from preexisting vessels; sprouting occurs when a “tip” cell migrates away from the preexisting vessels and other cells follow the path of this tip cell.

Specific growth factors, such as VEGF-A and bFGF, stimulate the proliferation, survival, and migration of quiescent endothelial cells in preexisting blood vessels. This stimulation results in the formation of new vessels during embryonic development and tumor growth. VEGF also promotes vasculogenesis, or the coalescence of new blood vessels from individual endothelial progenitor cells, that also occurs in tumors. VEGF and other factors such as SDF-1α can recruit circulating endothelial progenitor cells to tumors, where they can participate in new vessel growth. Additionally, myeloid lineage cells such as monocytes and macrophages are recruited by VEGF, SDF-1α, and other inflammatory factors and can modulate tumor angiogenesis and vasculogenesis.

A number of factors present in tumors promote the growth and guidance of both endothelium and neuronal cells, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), neuropilins, netrins, semaphorins, slit/robo, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and others. These factors have been shown to promote the development of both new blood vessels (angiogenesis) and nerves (neurogenesis). Circulating bone marrow-derived stem cells also contribute to both tumor neovascularization and neurogenesis.

Tumors express a number of neurotrophic factors that stimulate their own innervation. A key consequence of tumor innervation is cancer pain. Another consequence is tumor spread, or metastasis, along neural networks. Key neurotrophic factors such as nerve growth factor (NGF), artemin, netrin, BDNF, and even VEGF play important roles in this process. For example, NGF promotes cancer pain; an anti-NGF function-blocking antibody suppresses skeletal pain induced by prostate tumor cells growing in bone. Tumor necrosis factor α, a key factor produced by most tumor cells, also stimulates neuropathic pain.

Neuronal innervation also promotes tumor spread along axons. A number of neurotrophic factors promote tumor invasion and metastasis. For example, netrin promotes mammary epithelial cell invasion and migration. Netrin-1 also promotes tumor cell survival through its receptor Deleted in Colon Carcinoma. Another neurotrophic factor, artemin, promotes pancreatic cancer cell invasion along pancreatic nerves. BDNF may also stimulate spread of tumors along nerves. Increased BDNF is observed in several tumors, including orthotopic hepatocellular carcinoma, multiple myeloma, and neuroblastoma, where it is a marker of a poor prognosis. This neurotrophic factor promotes migration and growth of multiple myeloma cells. It also activates TrkB, which stimulates VEGF expression in neuroblastoma cells. Thus, neurogenesis in tumors contributes significantly to cancer pathology.

 

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