title: Tumor-stroma metabolic relationship based on lactate shuttle can sustain prostate cancer progression.
abstract: BACKGROUND
  Cancer cell adopts peculiar metabolic strategies aimed to sustain the continuous proliferation in an environment characterized by relevant fluctuations in oxygen and nutrient levels. Monocarboxylate transporters MCT1 and MCT4 can drive such adaptation permitting the transport across plasma membrane of different monocarboxylic acids involved in energy metabolism.
  
  
  METHODS
  Role of MCTs in tumor-stroma metabolic relationship was investigated in vitro and in vivo using transformed prostate epithelial cells, carcinoma cell lines and normal fibroblasts. Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression.
  
  
  RESULTS
  Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based on L-lactate shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive correlation between stromal MCT4 and tumor MCT1 expression.
  
  
  CONCLUSIONS
  Our data demonstrated that PCa progression may benefit of MCT1 expression in tumor cells and of MCT4 in tumor-associated stromal cells. Therefore, MCTs may result promising therapeutic targets in different phases of neoplastic transformation according to a strategy aimed to contrast the energy metabolic adaptation of PCa cells to stressful environments.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sanità
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.forename: Giuseppe Paradiso
authors.initials: GP
authors.lastname: Galatioto
authors.forename: Carlo
authors.initials: C
authors.lastname: Vicentini
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy. adriano.angelucci@univaq.it.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D020868:Gene Silencing; D006019:Glycolysis; D064593:Heterografts; D006801:Humans; D007773:Lactates / Q000378:metabolism*; D008297:Male; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C406962:SLC16A4 protein, human