title: A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer.
abstract: BACKGROUND
  In a malignant tumour, cancer cells are embedded in stromal cells, namely cancer-associated fibroblasts (CAFs). These CAFs are now accepted as important players in cancer dynamics, being involved in tumour growth and progression. Although there are various reports on the interaction between tumour and stromal cells, the clinico-pathological significance of this cross-talk is still largely unknown. In this study, we aimed to characterise the expression of key metabolic proteins involved in glucose transport, pyruvate/lactate shuttle system, glycolytic metabolism and fatty acid oxidation in CAFs and tumour cells in different stages of malignant transformation. We further aimed to contextualise the clinico-pathological significance of these protein expression profiles with reference to known prognostic indicators, including biochemical recurrence in pT stage.
  
  
  METHODS
  Prostate tissues were obtained from 480 patients with a median age of 64 years following radical prostatectomy with no previous hormonal therapy. Tissues were analysed for the expression of several key metabolism-related proteins in glands and surrounding fibroblasts by immunohistochemistry. Reliable markers of prognosis such as pT stage and biochemical recurrence were assessed for each case.
  
  
  RESULTS
  We observed that prostate cancer cells did not rely mainly on glycolytic metabolism, while there was a high expression of MCT4 and CAIX - in CAFs. This corroborates the hypothesis of the "Reverse Warburg effect" in prostate cancer, in which fibroblasts are under oxidative stress and express CAIX, an established hypoxia marker. We found that alterations in the expression of metabolism-related proteins were already evident in the early stages of malignant transformation, suggesting the continuing alteration of CAFs from an early stage. Additionally, and for the first time, we show that cases showing high MCT4 expression in CAFs with concomitant strong MCT1 expression in prostate cancer (PCa) cells are associated with poor clinical outcome, namely pT3 stage of the tumour.
  
  
  CONCLUSIONS
  In summary, this work demonstrates for the first time the clinico-pathological significance of the lactate shuttle in prostate cancer. It also suggests that other alterations in CAFs may be useful prognostic factors, and further supports the use of MCT1/MCT4 as targets for PCa therapy.
authors.forename: Nelma
authors.initials: N
authors.lastname: Pértega-Gomes
authors.forename: José R
authors.initials: JR
authors.lastname: Vizcaíno
authors.forename: Jan
authors.initials: J
authors.lastname: Attig
authors.forename: Sarah
authors.initials: S
authors.lastname: Jurmeister
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. fbaltazar@ecsaude.uminho.pt.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
mesh_terms: D001692:Biological Transport; D004734:Energy Metabolism; D005347:Fibroblasts / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D007610:Kallikreins / Q000097:blood; D019344:Lactic Acid / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000032:analysis; D009124:Muscle Proteins / Q000032:analysis; D009367:Neoplasm Staging; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D017154:Stromal Cells / Q000737:chemistry* / Q000473:pathology; D027981:Symporters / Q000032:analysis; D016896:Treatment Outcome; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D007610:Kallikreins; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D017430:Prostate-Specific Antigen; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human; C549870:KLK3 protein, human