Modeling Hypoxia Inducible. Factor-related Pathways in Tumours

Hypoxia can represent a challenging condition for survival at dierent biological scales, from cells to organisms. The eciency of the response to decreased oxygen availability is importantly related to the Hypoxia-Inducible Factors (HIFs) that regulate the transcription of hundreds of genes whose proteins are responsible for changes in several processes such as metabolism, in ammation, cell cycle, vascularisation. All these downstream responses contribute, on one side, to optimise the consumption of oxygen and, on the other side, to change the microenvironment in order to potentially create the conditions to favour oxygen delivery. The aims of this thesis are 1. to discuss the biological background of the main responses regulated by HIFs; 2. to review the mathematical models present in the literature that focused on various aspects of HIF activation or on specic HIF-related downstream actions; 3. to develop a new mathematical model that focuses on the oxygendependent regulation of HIF1 and HIF2, which are the most studied isoforms, comparing available experimental data on their temporal evolution in tumour cells with the results obtained integrating the proposed mathematical model; 4. to use the model to mathematically investigate the role of HIFs and hypoxia on in ammation via the activation of NFkB (Nuclear Factor k-light-chain-enhancer of activated B cells), examining possible scenarios when the dimensionless groups of parameters of the mathematical model change and discussing when hypoxic conditions may lead to acute or chronic in ammatory states; 5. to extend the model to the spatially dependent case to simulate some biological experiments characterised by the presence of an oxygen gradient activating a spatially dependent overexpression of HIF1; 6. to propose a biological mechanism that may link pH with HIF expression on the basis of experimental data; 4 5 7. to develop a mathematical model that describes the eect of HIF1 overexpression on the transition from aerobic to anaerobic metabolism, also considering the direct consequences on pH and thus on HIF expression.