Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors
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Céline Pinheiro1,2,3,4,*, Sara Granja1,2,*, Adhemar Longatto-Filho1,2,4,5, André M. Faria6, Maria C. B. V. Fragoso6,7, Silvana M. Lovisolo8, Antonio M. Lerário7, Madson Q. Almeida6,7, Fátima Baltazar1,2,*, Maria C. N. Zerbini9,*
1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
2ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
3Barretos School of Health Sciences Dr. Paulo Prata – FACISB, Barretos, Sao Paulo, Brazil
4Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil
5Laboratory of Medical Investigation (LIM-14), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
6Unidade 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
7Instituto do Câncer do Estado de São Paulo - ICESP, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
8Hospital Universitário, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
9Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
*These authors have contributed equally to this work
Céline Pinheiro, e-mail: [email protected]
Keywords: adrenocortical tumors, metabolic reprogramming, monocarboxylate transporter, Warburg effect
Received: May 09, 2015 Accepted: November 06, 2015 Published: November 16, 2015
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.
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