title: Organized metabolic crime in prostate cancer: The coexpression of MCT1 in tumor and MCT4 in stroma is an independent prognosticator for biochemical failure.
abstract: BACKGROUND
  Lactate import or export over cell membranes is facilitated by monocarboxylate transporters (MCTs) 1 and 4. Expression profiles can be markers of an oxidative or glycolytic phenotype. Descriptive studies and functional studies in neoplastic cells and fibroblasts in prostate cancer (PC) have suggested a distinct phenotype. We aimed to explore expression of MCT1 and MCT4 in PC cells and surrounding stroma in a large cohort. Additionally, we wanted to find out if distinct expression profiles were associated with biochemical failure-free survival (BFFS).
  
  
  METHODS
  Tissue microarrays were constructed from 535 patients with radical prostatectomies between January 1, 1995, and December 31, 2005. Immunohistochemistry was used to detect expression, and degrees of expression were evaluated semiquantitatively by 2 pathologists using light microscopy.
  
  
  RESULTS
  For MCT1, there was only epithelial expression, whereas there was a low level of expression of MCT4 in tumor and stroma. A total of 172 patients had a low expression of MCT1 in tumor and MCT4 in stroma. There were 232 patients who had a high expression of MCT1 and a low expression of MCT4 in stroma. Only 11 patients had a low tumoral MCT1 expression and a high stromal MCT4 expression, and 26 patients (5%) had a high expression of both. Patients with a high-high combination had a significantly reduced BFFS (P = 0.011), and when adjusting for other factors, its effect was significant and independent (HR = 1.99, CI 95%: 1.09-3.62; P = 0.024).
  
  
  CONCLUSIONS
  This study adds to the current understanding of the reversed Warburg effect to be a significant phenotype in PC. High coexpression of MCT1 in tumor and MCT4 in stroma is independently associated to a worse BFFS, and the strength of this association is as strong as having a Gleason score of ≥9.
authors.affiliation: Department of Clinical Medicine, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway; Department of Oncology, University Hospital of North Norway, Tromso. Electronic address: sigve.andersen@uit.no.
authors.forename: Sigve
authors.initials: S
authors.lastname: Andersen
authors.affiliation: Department of Pathology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Ørjan
authors.initials: Ø
authors.lastname: Solstad
authors.affiliation: Department of Pathology, University Hospital of North Norway, Tromso, Norway; Department of Medical Biology, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway.
authors.forename: Line
authors.initials: L
authors.lastname: Moi
authors.affiliation: Department of Clinical Medicine, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway; Department of Oncology, University Hospital of North Norway, Tromso.
authors.forename: Tom
authors.initials: T
authors.lastname: Donnem
authors.affiliation: Department of Clinical Medicine, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway.
authors.forename: Marte
authors.initials: M
authors.lastname: Eilertsen
authors.affiliation: Department of Clinical Medicine, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway; Department of Urology, University Hospital of North Norway, Tromso, Norway.
authors.forename: Yngve
authors.initials: Y
authors.lastname: Nordby
authors.affiliation: Department of Medical Biology, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway.
authors.forename: Nora
authors.initials: N
authors.lastname: Ness
authors.affiliation: Department of Pathology, University Hospital of North Norway, Tromso, Norway; Department of Medical Biology, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway.
authors.forename: Elin
authors.initials: E
authors.lastname: Richardsen
authors.affiliation: Department of Pathology, University Hospital of North Norway, Tromso, Norway; Department of Medical Biology, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway.
authors.forename: Lill-Tove
authors.initials: LT
authors.lastname: Busund
authors.affiliation: Department of Clinical Medicine, Translational Cancer Research Group, The Arctic University of Norway, Tromso, Norway; Department of Oncology, University Hospital of North Norway, Tromso.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Bremnes
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D006801:Humans; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D014408:Biomarkers, Tumor; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human
keywords: MCT1; MCT4; Monocarboxylate transporter; Prostate cancer; Stroma