Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumour aggressiveness

Monocarboxylate transporters (MCTs) are vital for intracellular pH homeostasis by extruding lactate from highly glycolytic cells. These molecules are key players of the metabolic reprogramming of cancer cells, and evidence indicates a potential contribution in urothelial bladder cancer (UBC) aggressiveness and chemoresistance.

However, the specific role of MCTs in the metabolic compartmentalization within bladder tumours, namely their preponderance on the tumour stroma, remains to be elucidated. Thus, we evaluated the immunoexpression of MCTs in the different compartments of UBC tissue samples (n=111), assessing the correlations among them and with the clinical and prognostic parameters. A significant decrease in positivity for MCT1 and MCT4 occurred from normoxic towards hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumour cells and in the tumour stroma. MCT1 staining in normoxic tumour areas, and MCT4 staining in hypoxic regions, in the tumour stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumour cells and in the tumour stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumour cells, was significantly associated with an unfavourable clinicopathological profile, and predicted lower overall survival rates among patients receiving platinum-based chemotherapy. Our results point to the existence of a multi-compartment metabolic model in UBC, providing evidence of a metabolic coupling between catabolic stromal and cancer cells' compartments, and the anabolic cancer cells. It is urgent to further explore the involvement of this metabolic coupling in UBC progression and chemoresistance.

Cell cycle (Georgetown, Tex. ). 2015 Dec 04 [Epub ahead of print]

Julieta Afonso, Lúcio L Santos, António Morais, Teresina Amaro, Adhemar Longatto-Filho, Fátima Baltazar

a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal. , c Department of Surgical Oncology , Portuguese Institute of Oncology (IPO) , Porto , Portugal. , e Department of Urology , Portuguese Institute of Oncology (IPO) , Porto , Portugal. , f Experimental Pathology and Therapeutics Research Center, Portuguese Institute of Oncology (IPO) , Porto , Portugal. , a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal. , a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal.

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