Angiogenesis refers to tissues vascularization process that entails the formation of novel blood capillary vessels from previous blood vessels. Angiogenesis happens as a usual biological process in wound healing, in ischemia response and in the reproductive cycle of female. However, abnormal angiogenesis may happen resulting to both malignant and non-malignant diseases. Abnormal angiogenesis is specifically associated with growth of tumor and the tumor progression to a metastatic phenotype. Angiogenesis is a requirement for solid tumor growth and development beyond 1-2mm. The process of angiogenesis in addition permits spread of tumor cells via the blood stream to detached sites.
Trough vascularity for tumor-derived, tumor growth angiogenic factors initiate expression of vascular endothelial growth factor (VEGF) to offer supply of oxygen by hypoxia-inducible factor (HIF) signaling activation in hypoxia-sensing cells. The tumor-related stromal cells and tumor cells secreted VEGF encourage vascular growth into tissues of hypoxic tumor to meet oxygen needs of the tumor. Sprouting process of angiogenesis, which is vascular sprouting, rises from former vessel and then creates a novel blood vessel. During the growth of the tumor, the highly aggressive process is initiated by vascular permeability and vessel dilation to permit proteins extravasation that comparatively disturb the endothelial wall basement membrane of pericytes, endothelial cells, preexisting blood vessel, and smooth vascular muscle cell that separate and drift to angiogenic stimuli.
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During angiogenesis endothelial cells are triggered to propagation and accumulated in tubular structures surrounding the developed walls of blood vessel. In further maturation of vascular network, capillaries change into bigger veins, arteries and vessels. Blood vessels enclosed by mural cells and endothelial cells can create vascular network in angiogenesis and vasculogenesis. Pericytes (Mural cells) has a heterogeneous cell population with ability of differentiation to mesenchymal cells such as osteoblasts, fibroblasts and smooth muscle cells. Tumor-related blood vessels are hemorrhagic and extremely divided. Stream of blood via these abnormal vessels is frequently disordered and obstruct chemotherapy delivery to tumor itself. The blood vessel formation is a regulated and complex process associating balance between different intercellular anti- and pro-angiogenic signaling pathways. In angiogenic switch there is an imbalance in the anti- and pro- angiogenic signaling levels of nutrients and oxygen supply for upholding development of tumor and permits spread of tumor cells via the blood stream to a detached sites.
Suppressing the anti-angiogenic factors and pro-angiogenic factors triggers angiogenesis for advanced tumor growth. Angiogenic switch activationis managed via secretion of cytokines and growth factors, tumor-suppressor genes inactivation, oncogene activation and specifically through tumor-related hypoxia. Oxygen tension is a feature of solid tumor which acts as VEGF inducer and contains an important role in neovascularization of tumor and spread of metastatic and is linked to the hypoxia-sensitive genes transcription. The genes transcription is controlled by the hypoxia inducible factors (HIFs), while hyproxia is the main HIF activation mediator, which is oncogene facilitated signaling through Mitogen-Activated Protein Kinases (MAPK) and phosphatidylinositide 3-kinases (PI3K), and activated HIFs as mutations can manage in the vHL (von Hippel Lindau) gene. Tumor angiogenesis offers channels via which metastasizes of cancer cells can happen.
A tumor of 1cm3 has cancer6 cells of about 109 which are consecutively supported by vascular endothelial cells of 107 to 108. Research studies have demonstrated that this co-population releases cancer cells of between 1 x 106 and 2 x 106 for every 24 hours in the circulation. Although majority of circulating cancer cells are removed by defense systems of the host, a few survive following their lodging in detached organs, they then remain dormant up to when angiogenesis happens.
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