Modeling hypoxia-related inflammation scenarios

Cells respond to hypoxia via the activation of three isoforms of Hypoxia Inducible Factors (HIFs), that are characterized by different activation times. HIF overexpression has many effects on cell behavior, such as change in metabolism, promotion of angiogenic processes and elicitation of a pro-inflammatory response. These effects are driving forces of malignant progression in cancer cells. In this work we study in detail hypoxia-induced dynamics of HIF1a and HIF2a, which are the most studied isoforms, comparing available experimental data on their evolution in tumor cells with the results obtained integrating the deduced mathematical model. Then, we examine the possible scenarios that characterize the link between hypoxia and inflammation via the activation of NFkB (Nuclear Factor k-light-chain-enhancer of activated B cells) when the dimensionless groups of parameters of the mathematical model change. In this way we are able to discuss why and when hypoxic conditions lead to acute or chronic inflammatory states.