Cancer development results from the selection of cells with mutation(s) that provide survival and proliferative advantages. Normal barriers to proliferation are overcome as clones adapt to an ever changing hostile microenvironment, where low oxygen tension, low glucose levels, and an acidic extracellular pH (all of which increase genetic instability) are found. The hypoxia inducible factors, HIF-1 and HIF-2, are upregulated in response to these conditions. This could occur by constitutive activation of PI3K signaling or inactivating mutations in, for example, the von Hippel–Lindau tumor suppressor, VHL [35-37], which normally deacetylates HIF-1α, leading to HIF-1α polyubiquitination and proteasomal degradation [38]. HIFs trans activate genes mediating proliferation, angiogenesis, intermediate metabolism (glycolysis) and pH regulation, which promote tumor development [39].
HIF-1α stimulates production of growth factors, such as transforming growth factor β (TGF-β), insulin-like growth factor 2, interleukin-6 (IL-6), interleukin-8, macrophage migration inhibitory factor (MIF), and growth factor receptors, such as the epidermal growth factor receptor (EGFR), resulting in continuous proliferative signaling. In the hypoxic environment, constitutive activation of these signaling pathways (e.g., Ras [1] and PI3K [2]) stabilizes HIF-1 and may result in “oncogene addiction” that persists through the transition from adenoma to carcinoma. In the case of PI3K, constitutive activation may result from the appearance of mutations in tumor suppressor genes (e.g., the phosphatase and tensin homolog [PTEN]), from activating mutations in the PI3K complex itself, or from aberrant signaling in receptor tyrosine kinases [40].
