Modelling of pH regulation in tumor cells & surrounding tissue. Influence on cancer cell migration
A recent approach in cancer therapy is based on the role of tumor microenvironment in determining cancer malignancy. It has been suggested (Hanahan & Weinberg 2011, Gatenby & Gillies 2007) that environmental conditions may drive the selection of the cancerous phenotype. Hypoxia and acidity, for instance, are factors that can trigger the progression from benign to malignant growth (Webb et al. 2011). To survive in their environment, tumor cells upregulate certain proton extrusion mechanisms. This boosts apoptosis of normal cells and thus allows the neoplastic tissue to further extend into the space available. Tumor acidification was recognized as an intrinsic property of both poor vasculature and altered cancer cell metabolism. Moreover, the pH directly influences the metastatic potential of tumor cells (Martinez-Zaguilan et al. 1996, Stock & Schwab 2009).
In this project we will investigate how changes in intra- and extracellular pH influence tumor cell migration and invasion. To this aim we will use multiscale mathematical models involving on the microscopic scale the intracellular proton dynamics (via ordinary or stochastic differential equations) and using on the macroscale reaction-diffusion(-transport) equations for the evolution of the tumor cell population in interaction with normal cells and extracellular protons. Thereby, an important issue is the regulation of protons inside the cells and in the peritumoral environment. Physiological experiments on tumor cell lines and multicellular spheroids will provide quantitative information (e.g., absolute changes in intracellular pH, extracellular surface membrane pH, intracellular metabolite concentration for glucose, pyruvate, lactate) to be fed into our models. The results from these models will be tested by experiments (including measurements of cell migration and invasion). An additional aim of the mathematical modeling is to identify -via numerical simulations and qualitative analysis- possible therapy strategies, for instance by increasing the pH in the peritumoral region in order to render the tumor sensitive to further treatment like ionizing radiation.
D. Hanahan and R.A. Weinberg. Hallmarks of cancer: The next generation. Cell 144 (2011) , pp.646-674.
Gatenby, R.A., and Gillies, R.J., Glycolysis in cancer: a potential target for therapy, Int. J. Biochem. Cell Biol. 39 (2007), pp.1358-1366.
Martinez-Zaguilan, R, Seftor, E.A., Seftor, R.E.B., Chu, Y., Gillies, R.J., and Hendrix, M.J.C., Acidic pH enhances the invasive behavior of human melanoma cells, Clin. Exp. Metastasis 14 (1996), pp.176-186.
Stock, C., and Schwab, A., Protons make tumor cells move like clockwork, European J. Physiology 458 (2009), pp.981-992.
Webb, B.A., Chimenti, M., Jacobson, M.P., and Barber, D., Dysregulated pH: a perfect storm for cancer progression, Nature Reviews Cancer 11 (2011), pp.671-677.