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RECIPROCAL METABOLIC REPROGRAMMING THROUGH LACTATE SHUTTLE COORDINATELY INFLUENCES TUMOR-STROMA INTERPLAY.
MedLine Citation:
PMID:  22850421     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Cancer associated fibroblasts (CAFs) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer (PCa) cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia (HPFs) revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming towards a Warburg phenotype occurred as a result of contact with PCa cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, PCa cells, upon contact with CAFs, were reprogrammed towards aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia inducible factor HIF1, which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. PCa cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacological inhibition of MCT1-mediated lactate upload dramatically affected PCa cells survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability.
Authors:
Tania Fiaschi; Alberto Marini; Elisa Giannoni; Maria L Taddei; Paolo Gandellini; Alina De Donatis; Michele Lanciotti; Sergio Serni; Paolo Cirri; Paola Chiarugi
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-31
Journal Detail:
Title:  Cancer research     Volume:  -     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-8-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department Biochemical Sciences, University of Florence.
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