Oncogenes and angiogenesis: Signaling three-dimensional tumor growth

Three-dimensional tumor growth is dependent on the perpetual recruitment of host blood vessels to the tumor site, This recruitment process (mainly via angiogenesis) is thought to be triggered, at least in part, by the very sa me set of genetic alterations (activated oncogenes, inactivated/lost tumor suppressor genes) as those responsible for other aspects of malignant trans formation (e,g,, aberrant mitogenesis, resistance to apoptosis), Potent onc ogenes are able to deregulate expression of both angiogenesis stimulators a nd inhibitors in cancer cells. For example, mutant uas expression is associ ated with increased production of vascular endothelial growth factor (VEGF) and downregulation of thrombospondin-l (TSP-1). Upregulation of VEGF and a ngiogenesis can also be induced by constitutive activation of other oncogen ic proteins (e,g., EGFR, Raf, MEK, PI3K) acting at various levels on the Ra s signaling pathway. The mode and the magnitude of such proangiogenic influ ences can be significantly modified by cell type (fibroblastic or epithelia l origin), epigenetic factors (hypoxia, changes in cell, density), and/or p resence of additional genetic lesions (e,g,, pre-ceding loss of p16 or p53 tumor suppressor genes). Activated oncogenes (e,g,, uas, src, HER-2) induce co-expression of angiogenic properties concomitantly with several highly s electable traits (increased mitogenesis, resistance to apoptosis), a circum stance that may accelerate selection of the angiogenic phenotype at the cel l population level. On the other hand oncogene-induced reduction in growth requirements may also endow tumor cells with a diminished (albeit not abrog ated) dependence on (close) proximity to blood vessels, i,e,, with reduced vascular dependence, Thus, oncogenes can impact several interconnected aspe cts of cellular growth, survival, and angiogenesis. Experimental evidence s uggests that, in principle, many of these properties (including angiogenesi s) can be simultaneously suppressed (and tumor stasis or regression induced ) by effective use of the specific oncogene antagonists and signal transduc tion inhibitors.