title: Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors.
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.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.|Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, Sao Paulo, Brazil.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil.
authors.forename: Céline
authors.initials: C
authors.lastname: Pinheiro
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Granja
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil.|Laboratory of Medical Investigation (LIM-14), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
authors.affiliation: 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.
authors.forename: André M
authors.initials: AM
authors.lastname: Faria
authors.affiliation: 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.|Instituto do Câncer do Estado de São Paulo - ICESP, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Maria C B V
authors.initials: MC
authors.lastname: Fragoso
authors.affiliation: Hospital Universitário, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Silvana M
authors.initials: SM
authors.lastname: Lovisolo
authors.affiliation: Instituto do Câncer do Estado de São Paulo - ICESP, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Lerário
authors.affiliation: 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.|Instituto do Câncer do Estado de São Paulo - ICESP, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
authors.affiliation: Departamento de Patologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Zerbini
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018246:Adrenocortical Adenoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018268:Adrenocortical Carcinoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis; D051926:Basigin / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis; D018572:Disease-Free Survival; D004734:Energy Metabolism; D005260:Female; D051272:Glucose Transporter Type 1 / Q000032:analysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D027501:Monocarboxylic Acid Transporters / Q000032:analysis; D009124:Muscle Proteins / Q000032:analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D027981:Symporters / Q000032:analysis; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000951:Antigens, Neoplasm; D051926:Basigin; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D051272:Glucose Transporter Type 1; D018960:Hyaluronan Receptors; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C497886:BSG protein, human; C497483:CD44 protein, human; C406962:SLC16A4 protein, human; C490427:SLC16A7 protein, human; C495677:SLC2A1 protein, human; C089226:CA9 protein, human
keywords: Warburg effect; adrenocortical tumors; metabolic reprogramming; monocarboxylate transporter