Figure 6From: Hypoxia-inducible factor (HIF) network: insights from mathematical modelsOpportunities for further modelling work: HIF crosstalk to mTOR and NFκB in cancer and inflammation. Hypoxia, the cellular condition when oxygen demand exceeds oxygen supply (1) is present in several physiological and pathophysiological processes including inflammation (2) were hypoxia is induced as a result of the highly metabolically active inflammatory cells and reduced blood supply associated with a disrupted vasculature; and cancer (3) were the highly proliferative cancer cells can be very far away from the vasculature. NFκB is classically activated by inflammatory stimulus (4) and has recently been appreciated to be regulated by hypoxia (5), both of these stimulus are present in regions of chronic inflammation and can also activate HIF (6,7). Furthermore, these two transcription factors show a significant degree of crosstalk with NFκB transcriptionally regulating HIF (8) and HIF regulating NFκB activity (9). mTOR is affected by hypoxia at multiple levels (10) and is activated in cancer (11). HIF is overexpressed in cancer, due to both tumour hypoxia (6) and mutations in tumour suppressor genes (12). Importantly, mTOR transcriptionally regulates HIF in response to growth factors (13) and HIF regulates for growth factor receptors and adaptor proteins which can affect mTOR signalling (14). While most of the mechanisms of the effect of cellular hypoxia on the HIF response have been modelled (15, continuous lines), the HIF/hypoxia crosstalk to NFκB and mTOR and the outcome of the interaction of these pathways in inflammation and tumour development are still open opportunities for further modelling research (16,17, dashed lines).Back to article page