Metabolic reprogramming in gastric cancer

Abstract

Globally, gastric cancer claims around 800,000 lives per year. As many patients present at an advanced stage of disease, prognosis remains poor for most patients, with five-year survival rates of less than 30%. As many patients show only limited short-term benefits from current therapeutic regimes, there is a clear need for improved understanding of the molecular mechanisms that drive the development and spread of gastric cancer. In this context, the role of the tumour microenvironment in cancer development and the potential for new forms of therapeutic intervention has become a field of increasing interest in many areas of cancer research. It is now well established that the development and progression of gastric tumours is facilitated by reciprocal communication between cancer cells, and cells within the surrounding tissue. In this study we focus our investigation on the mechanisms and consequences of paracrine communication between gastric cancer cells and different populations of stromal myofibroblasts, which are prevalent within the cancer microenvironment and form a significant proportion of many solid tumours. Previous studies show that myofibroblasts derived from gastric tumours (CAMs) have inherently different profiles of gene expression, compared to patient matched adjacent tissue myofibroblasts (ATMs), or normal tissue myofibroblasts (NTMs). Given these differences, we were interested to know if specific myofibroblast populations respond differently to signals from cancer cells; or conversely, if they exhibit differential ability to facilitate pro- tumourogenic changes in gastric cancer cells. Using a combination of bioinformatics and experimental techniques we demonstrate that CAM-conditioned media induces distinct changes in the gene expression profiles and metabolic activity of AGS gastric cancer cells. Significantly, these changes were not observed following exposure to conditioned media derived from either ATM or NTM cells. Conversely, CAM cells were found to have higher levels of GLUT1 and MCT4 expression with a corresponding reduction in mitochondrial activity compared to NTM cell lines. Finally, initial analysis of CAM imposed changes in AGS gene-expression suggests changes may reflect patient prognosis or stage of tumour development, implying future potential for patient stratification. In conclusion, data from this study shows that activated CAMs are robustly programmed by cancer cells to facilitate optimal conditions for tumour growth. Therefore, further analysis of this system may provide much needed options for improved therapeutic intervention and precision medicine