Gene Expression Under Combined Hypoxia And Acidosis In Chondrosarcoma

Abstract

Chondrosarcomas are the second most common cause of bone cancer and are removed surgically with wide margins. On recurrence, they are resistant to chemo and radiation therapy and new treatment options are critically required. This tumor type produces hyaline cartilage, a cartilage normally formed under hypoxic and acidic environment due to lack of vasculature in cartilage. Paradoxically, chondrosarcomas arise in the well vascularized, oxygen rich environment of the bone. Hypoxia and acidosis are two stressors where the cellular effects are typically reported separately even though cells experience combined effects of hypoxia and acidosis. Given the mechanistic links between hypoxia and acidosis we hypothesized that gene expression profiles will be differentially changed when chondrosarcoma cells were exposed to individual compared to combined stressors. We investigated expression of four genes expressed during cartilage and cartilage tumor formation in primary chondrocytes and two grade II chondrosarcoma cell lines, SW1353 and JJ012. Two genes, PTH1R and SOX9 are known to respond to hypoxia and acidosis separately. Two genes, IDH1 and IDH2, are mutated in chondrosarcoma cell lines JJ012 and SW1353 respectively. These mutations confer a condition of false hypoxia on the cells through stabilization of HIF-1α. The result is chondrosarcoma cells metabolize glycolytically through aerobic glycolysis. How the cells respond to hypoxia and acidosis is of considerable interest as metabolically the cells are molecularly predisposed to these conditions. Our gene expression data found that combined hypoxia and extracellular acidosis alter gene expression compared to either stressor alone. Cells showed gene specific responses to stressors that were cell type specific likely indicating influence on gene expression regulatory sequences. The importance of this work is highlighting that conditions under which cells are investigated is crucial and should be considered when measuring cell response to in vitro treatment exposures.