Oncogenes and angiogenesis: signaling three-dimensional tumor growth.

摘要: Three-dimensional tumor growth is dependent on the perpetual recruitment of host blood vessels to site. This process (mainly via angiogenesis) thought be triggered, at least in part, by very same set genetic alterations (activated oncogenes, inactivated/lost suppressor genes) as those responsible for other aspects malignant transformation (e.g., aberrant mitogenesis, resistance apoptosis). Potent oncogenes are able deregulate expression both angiogenesis stimulators and inhibitors cancer cells. For example, mutant ras associated with increased production vascular endothelial factor (VEGF) downregulation thrombospondin-1 (TSP-1). Upregulation VEGF can also induced constitutive activation oncogenic proteins EGFR, Raf, MEK, PI3K) acting various levels Ras signaling pathway. The mode magnitude such pro-angiogenic influences significantly modified cell type (fibroblastic or epithelial origin), epigenetic factors (hypoxia, changes density), and/or presence additional lesions preceding loss p16 p53 genes). Activated ras, src, HER-2) induce co-expression angiogenic properties concomitantly several highly selectable traits (increased apoptosis), a circumstance that may accelerate selection phenotype population level. On hand oncogene-induced reduction requirements endow cells diminished (albeit not abrogated) dependence (close) proximity vessels, i.e., reduced dependence. Thus, impact interconnected cellular growth, survival, angiogenesis. Experimental evidence suggests that, principle, many these (including simultaneously suppressed (and stasis regression induced) effective use specific oncogene antagonists signal transduction inhibitors.