Associação Portuguesa de Investigação em Cancro
The metabolic reprogramming of adult adrenocortical tumors is associated with patient’s prognosis
The metabolic reprogramming of adult adrenocortical tumors is associated with patient’s prognosis
Most tumors show an increase in glucose consumption, which is metabolized resulting in lactic acid production. Consequently, the lactate formed is transported out of the tumor cells by a protein complex formed by monocarboxylate transporters (MCT) and CD147. The hyperglicolytic phenotype is characterized by the expression of the glucose transporter GLUT1, the pH regulator CAIX and lactate transporters (MCT1 and MCT4), and is associated with tumor progression and aggressiveness. In this study, we assessed the expression of the above mentioned proteins in adrenocortical neoplasia samples and the respective association with the clinicopathological data. We found that the plasma membrane expression of proteins associated with the glycolytic phenotype as GLUT1, MCT1 and CAIX, are highly expressed in the more aggressive tumors and its expression is associated with a poor prognosis of these patients, whereas cytoplasmic expression of CD147 and CAIX is related to parameters that favor a good prognosis. The results of this work show that the metabolic reprogramming of adrenocortical tumors, favoring the hyperglicolitic phenotype, is associated with poor prognosis.
Authors and Affiliations:
Céline Pinheiro 1,2,3,4,*, Sara Granja 1,2,*, Adhemar Longatto-Filho 1,2,4,5, André M. Faria 6, Maria C. B. V. Fragoso 6,7, Silvana M. Lovisolo 8, Antonio M. Lerário 7, Madson Q. Almeida 6,7, Fátima Baltazar 1,2,*, Maria C. N. Zerbini 9,*
1.Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
2.ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
3.Barretos School of Health Sciences Dr. Paulo Prata – FACISB, Barretos, Sao Paulo, Brazil
4.Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil
5.Laboratory of Medical Investigation (LIM-14), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
6.Unidade de Suprarrenal, Disciplina de Endocrinologia e Metabologia, Laboratório de Hormônios e Genética Molecular LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
7.Instituto do Câncer do Estado de São Paulo - ICESP, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
8.Hospital Universitário, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
9.Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
*These authors have contributed equally to this work
Abstract:
Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients’ clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.
Journal:Oncotarget
