Prognostic value of MCTs expression in oral cavity carcinomas

Oral cavity carcinomas (OCC) are one of the most common type of head and neck squamous cell carcinoma, which is in turn one of most common type of cancer worldwide. The fact that it is generally diagnosed at advanced disease stages contributes to poor survival of patients, besides the progress in the treatment options along the last years. Therefore, becomes urgent to identify new biomarkers that could contribute to increase the effectiveness of the treatments. As most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates, proteins and enzymes related with the glycolytic metabolism are generally up-regulated in these cells. In the present study, we analysed the expression of monocarboxylate transporters (MCTs) 1, 2 and 4 and other glycolytic metabolism-related proteins, in a series of OCC human samples, and investigated the correlation with clinicopathological parameters and a possible association with prognosis. We found overexpression of MCT1/4, CD147, GLUT1 and CAIX in the tumor samples supporting the presence of a hyper-glycolytic phenotype in OCC and, importantly, we observed that a specific combination of positive MCT1/4 and negative MCT2 was associated with poor patient survival. The results of this work show that the metabolic reprograming of these tumors may contribute to the poor prognosis of the patients, opening a way for further studies about therapy approaches that could use the glycolytic phenotype-related features to improve the treatment of these patients.

Autores e Afiliações:

Susana Sousa^a,b,*,#, Sara Granja^a,b,#, Céline Pinheiro^a,b,c,d, Daniela Fernandes^a,b, Adhemar Longatto-Filho^a,b,d,e, Ana Carolina Laus^d, Cira Danielle Casado Alves^f, J. M. Suárez-Peñaranda^g, Mario Pérez-Sayáns^h, Andre Lopes Carvalho^d,f, Fernando C. Schmitt^i,j,k, Abel García-García^h and Fatima Baltazar^a,b

^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

^c Barretos School of Health Sciences Dr. Paulo Prata – FACISB, Barretos, Sao Paulo, Brazil

^d Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

^e Laboratory of Medical Investigation (LIM-14), Faculdade de Medicina 10 da Universidade de, S~ao Paulo, Brazil

^f Head and Neck Surgery Department, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil

^g Department of Pathology and Forensic Sciences, University Hospital and School of Medicine of Santiago de Compostela, Santiago de Compostela, A Coruña, Spain

^h Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Dentistry, Health Research Institute of Santiago (IDIS), Santiago de Compostela, A Coru~na, Spain

ⁱ IPATIMUP - Institute of Molecular Pathology and Immunology of University of Porto, Porto, Portugal

^j Medical Faculty of the University of Porto, Porto, Portugal

^k Department of Pathology and Medicine, Laboratoire National de Sante, Dudelange, Luxembourg

^# These authors equally contributed to this work

^* Present affiliation: Manchester Cancer Research Centre, The University of Manchester, Manchester, United Kingdom

Abstract:

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer. The majority of patients present advanced stage disease and has poor survival. Therefore, it is imperative to search for new biomarkers and new alternative and effective treatment options. Most cancer cells rely on aerobic glycolysis to generate energy and metabolic intermediates. This phenotype is a hallmark of cancer, characterized by an increase in glucose consumption and production of high amounts of lactate. Consequently, cancer cells need to up-regulate many proteins and enzymes related with the glycolytic metabolism. Thus, the aim of this study was to characterize metabolic phenotype of oral cavity cancers (OCC) by assessing the expression pattern of monocarboxylate transporters (MCTs) 1, 2 and 4 and other proteins related with the glycolytic phenotype. Material and Methods: We evaluated the immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX in 135 human samples of OCC and investigated the correlation with clinicopathological parameters and the possible association with prognosis. Results: We observed that all proteins analysed presented significantly higher plasma membrane expression in neoplastic compared to non-neoplastic samples. MCT4 was significantly associated with T-stage and advanced tumoral stage, while CD147 was significantly correlated with histologic differentiation. Interestingly, tumors expressing both MCT1 and MCT4 but negative for MCT2 were associated with shorter overall survival. Conclusion: Overexpression of MCT1/4, CD147, GLUT1 and CAIX, supports previous findings of metabolic reprograming in OCC, warranting future studies to explore the hyper-glycolytic phenotype of these tumors. Importantly, MCT expression revealed to have a prognostic value in OCC survival.

Revista: Cell Cycle

Link: http://www.tandfonline.com/doi/full/10.1080/15384101.2016.1188239