Abstract 437: A putative role of hypoxia in development of de novo chemoresistance

Abstract

Abstract In this work we built a computational model that explores the concept of hypoxia induced de novo chemoresistance. We propose that the hypoxic regions of solid tumors not only protect tumor cells from chemotherapy (environmental resistance) but also are the birthplace of de novo multidrug phenotypically chemoresistant cells. These phenotypically resistant cells would be rare in an untreated tumor due to hypoxia and low external pH (pHe) induced quiescence in the environment where they grow. These cells, however, would be subject to a selective pressure for survival by disruption of apoptotic pathways and overexpression of hypoxia-inducible factors which are known to activate multidrug resistance genes, among other pro-survival mechanisms. Tumor cells under chronic hypoxic conditions are also subject to higher genetic instability than tumor cells in normoxia, due in part to the decrease in the expression of homologous recombination proteins, what could also increase the rate of evolution towards a multi-drug chemoresistant phenotype. In the presence of therapy, the sensitive cells (environmentally or phenotypically) are removed from the tumor, reducing hypoxia, normalizing pHe and allowing the phenotypically chemoresistant subpopulation of cells to grow and re-populate the tumor. This work extends our recent chemoresistance model by adding a representation of HIF-1alpha gene, whose response to hypoxia may change due to mutation from varying thresholds until constant activation or deactivation. The expression of this gene is linked to survival in low pHe, expression of multidrug resistance gene (MDR-1) and glycolysis. Our simulations show that HIF-1alpha expression is selected towards constitutive activation due to its increase in glycolysis and low pHe resistance, which in turn increase tumor survival and invasion. Multi-drug resistance is also increased in such cells as a consequence of the selection for these two phenotypes. This work proposes a mechanism for development of chemoresistance in absence of drug which is different from acquired resistance since the selection for this phenotype is not imposed by the drug itself but as side effect of the selection for survival in hypoxia and low pHe. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 437.