title: Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness.
abstract: 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 tumors, namely their preponderance on the tumor 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 toward hypoxic regions. Significant associations were found between the expression of MCT4 in hypoxic tumor cells and in the tumor stroma. MCT1 staining in normoxic tumor areas, and MCT4 staining in hypoxic regions, in the tumor stroma and in the blood vessels were significantly associated with UBC aggressiveness. MCT4 concomitant positivity in hypoxic tumor cells and in the tumor stroma, as well as positivity in each of these regions concomitant with MCT1 positivity in normoxic tumor 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.
authors.affiliation: a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal.|b ICVS/3B's - PT Government Associate Laboratory , Braga/Guimarães , Portugal.
authors.forename: Julieta
authors.initials: J
authors.lastname: Afonso
authors.affiliation: c Department of Surgical Oncology , Portuguese Institute of Oncology (IPO) , Porto , Portugal.|d Faculty of Health Sciences, University Fernando Pessoa (UFP) , Porto , Portugal.
authors.forename: Lúcio L
authors.initials: LL
authors.lastname: Santos
authors.affiliation: e Department of Urology , Portuguese Institute of Oncology (IPO) , Porto , Portugal.
authors.forename: António
authors.initials: A
authors.lastname: Morais
authors.affiliation: f Experimental Pathology and Therapeutics Research Center, Portuguese Institute of Oncology (IPO) , Porto , Portugal.
authors.forename: Teresina
authors.initials: T
authors.lastname: Amaro
authors.affiliation: a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal.|b ICVS/3B's - PT Government Associate Laboratory , Braga/Guimarães , Portugal.|g Laboratory of Medical Investigation (LIM 14), Faculty of Medicine, São Paulo State University , São Paulo , Brazil.|h Molecular Oncology Research Center, Barretos Cancer Hospital , São Paulo , Brazil.
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
authors.affiliation: a Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho , Braga , Portugal.|b ICVS/3B's - PT Government Associate Laboratory , Braga/Guimarães , Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000071231:Carbonic Anhydrase IX; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human
keywords: chemoresistance; metabolic compartments; monocarboxylate transporters; tumor stroma; urothelial bladder cancer