title: Reprogramming energy metabolism and inducing angiogenesis: co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas.
abstract: BACKGROUND
  Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior.
  
  
  METHODS
  The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients' clinicopathological parameters.
  
  
  RESULTS
  Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis.
  
  
  CONCLUSIONS
  The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4710-057, Portugal. celinepinheiro@gmail.com.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. celinepinheiro@gmail.com.|Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil. celinepinheiro@gmail.com.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil. celinepinheiro@gmail.com.
authors.forename: Céline
authors.initials: C
authors.lastname: Pinheiro
authors.affiliation: Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil. eduardoag@gmail.com.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil. eduardoag@gmail.com.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Garcia
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4710-057, Portugal. filipasantos@ecsaude.uminho.pt.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. filipasantos@ecsaude.uminho.pt.
authors.forename: Filipa
authors.initials: F
authors.lastname: Morais-Santos
authors.affiliation: Department of Pathology of the School of Medicine of the Federal University of Goiás, Goiânia, Go, Brazil. marisemoreira7@gmail.com.
authors.forename: Marise A R
authors.initials: MA
authors.lastname: Moreira
authors.affiliation: Department of Pathology of the School of Medicine of the Federal University of Goiás, Goiânia, Go, Brazil. fabim12@gmail.com.
authors.forename: Fábio M
authors.initials: FM
authors.lastname: Almeida
authors.affiliation: Hospital Araújo Jorge, Goiânia, Go, Brazil. lfjube@hotmail.com.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Jubé
authors.affiliation: Hospital Araújo Jorge, Goiânia, Go, Brazil. geraldoestudantedelogosofia@yahoo.com.br.
authors.forename: Geraldo S
authors.initials: GS
authors.lastname: Queiroz
authors.affiliation: Hospital Araújo Jorge, Goiânia, Go, Brazil. elcanpa@yahoo.com.br.
authors.forename: Élbio C
authors.initials: ÉC
authors.lastname: Paula
authors.affiliation: Instituto Nacional de Ciência e Tecnologia do HPV (INCT-HPV), Sao Paulo, Brazil. mandreoli@incthpv.org.br.|Santa Casa de São Paulo Medical School, São Paulo, Brazil. mandreoli@incthpv.org.br.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Andreoli
authors.affiliation: Instituto Nacional de Ciência e Tecnologia do HPV (INCT-HPV), Sao Paulo, Brazil. luisa.villa@icesp.org.br.|Department of Radiology, Center on Translational Oncology Investigation, São Paulo State Cancer Institute, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil. luisa.villa@icesp.org.br.|Santa Casa de São Paulo Medical School, São Paulo, Brazil. luisa.villa@icesp.org.br.
authors.forename: Luisa L
authors.initials: LL
authors.lastname: Villa
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4710-057, Portugal. longatto16@hotmail.com.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. longatto16@hotmail.com.|Instituto Nacional de Ciência e Tecnologia do HPV (INCT-HPV), Sao Paulo, Brazil. longatto16@hotmail.com.|Laboratory of Medical Investigation (LIM-14), School of Medicine, University of Sao Paulo, Sao Paulo, Brazil. longatto16@hotmail.com.
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, 4710-057, Portugal. fbaltazar@ecsaude.uminho.pt.|ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. fbaltazar@ecsaude.uminho.pt.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins; D009389:Neovascularization, Pathologic / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D027501:Monocarboxylic Acid Transporters; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A