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. Author manuscript; available in PMC: 2013 Sep 1.
Published in final edited form as: Trends Biochem Sci. 2012 Jul 18;37(9):364–372. doi: 10.1016/j.tibs.2012.06.004

Figure 3.

Figure 3

The switch from HIF-1- to HIF-2-dependent transcription during chronic hypoxia in solid tumors. (a) The diffusion limitation of oxygen results in oxygen gradients within solid tumors (i). Acute hypoxia caused by vessel occlusion or rapid tumor growth promotes induction of both HIF-1α and -2α (ii); however, HIF-1 is the major driver of the acute response. This causes activation of the HIF-1 transcriptional program, which promotes alleviation of hypoxia through angiogenesis and/or reperfusion, or (iii) cell death (broken circles), depending on the mutational landscape of the tumor cells. Alternatively, chronic hypoxia (iv) can increase HAF and HIF-2α levels, mediating a switch to HIF-2-dependent transcriptionthat promotes tumor adaptation, proliferation and progression. (b) The temporal regulation of HIF-1α (blue line), HIF-2α (green line) and HAF (red line) in response to prolonged hypoxic exposure. The window in which the HIF-1α to HIF-2α switch occurs is indicated by broken vertical lines.