title: Lactate transporters and vascular factors in HPV-induced squamous cell carcinoma of the uterine cervix.
abstract: BACKGROUND
  Tumour microenvironment is a fundamental aspect of tumour behaviour, modulating important events as cancer cell migration and invasion, as well as angiogenesis and metastisation. Among other microenvironment features, hypoxia and acidity play important roles in this modulation. As the metabolic reprogramming of cancer cells induces extracellular acidity, which in turn induces angiogenesis, and hypoxia induces both the metabolic reprogramming and angiogenesis, the present study aims to evaluate the immunohistochemical expression of a variety of metabolic and vascular markers as common targets of the hypoxic microenvironment in a series of cervical squamous cells carcinoma, as well as using an in vitro 3D culture model.
  
  
  METHODS
  Immunohistochemical expression of MCT1, MCT4, CD147, GLUT1 and CAIX was assessed in a series of 28 chronic cervicitis, 34 LSIL, 29 HSIL, 38 cases of squamous cells carcinoma (SCC), as well as in in vitro 3D culture of keratinocytes expressing HPV genes. Furthermore, VEGF family members' expression was assessed in the SCC cases. The expression profiles were associated with patients' clinicopathological parameters.
  
  
  RESULTS
  We found an increase of MCT4 expression along progression to malignancy in cervical samples. Also, MCT4 was associated with CD147 and CAIX expression. VEGF-A expression was more frequently found in cases without MCT1 expression. Both MCT4 and CD147 were more frequently expressed in younger patients at diagnosis while no associations were found between VEGF family and clinicopathological parameters. Finally, we show evidence for the upregulation of MCT4, as well as CD147 and CAIX, after HPV transfection.
  
  
  CONCLUSIONS
  The results herein presented point at MCT4 as a promising therapeutic target in squamous cells carcinoma of the uterine cervix. Importantly, we show a possible association between lactate transport and angiogenesis, which should be further explored.
authors.forename: Céline
authors.initials: C
authors.lastname: Pinheiro
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Garcia
authors.forename: Filipa
authors.initials: F
authors.lastname: Morais-Santos
authors.forename: Cristovam
authors.initials: C
authors.lastname: Scapulatempo-Neto
authors.forename: Allini
authors.initials: A
authors.lastname: Mafra
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.forename: Enrique
authors.initials: E
authors.lastname: Boccardo
authors.forename: Luisa L
authors.initials: LL
authors.lastname: Villa
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. longatto16@hotmail.com.
authors.forename: Adhemar
authors.initials: A
authors.lastname: Longatto-Filho
mesh_terms: D015415:Biomarkers; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics; D052161:Human papillomavirus 18 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D030361:Papillomavirus Infections / Q000150:complications*; D010455:Peptides / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D015415:Biomarkers; D036341:Intercellular Signaling Peptides and Proteins; D027501:Monocarboxylic Acid Transporters; D010455:Peptides; C021266:vascular factor