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Tumor and Stem Cell Biology

Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay

Tania Fiaschi, Alberto Marini, Elisa Giannoni, Maria Letizia Taddei, Paolo Gandellini, Alina De Donatis, Michele Lanciotti, Sergio Serni, Paolo Cirri and Paola Chiarugi
Tania Fiaschi
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Alberto Marini
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Elisa Giannoni
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Maria Letizia Taddei
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Paolo Gandellini
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Alina De Donatis
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Michele Lanciotti
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Sergio Serni
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Paolo Cirri
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Paola Chiarugi
Authors' Affiliations: 1Department of Biochemical Sciences, Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”; 2Department of Urology, University of Florence, Florence, Italy; and 3Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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DOI: 10.1158/0008-5472.CAN-12-1949 Published October 2012
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Abstract

Cancer-associated fibroblasts (CAF) 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 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 revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer 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, prostate cancer cells, upon contact with CAFs, were reprogrammed toward 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 1 (HIF1), which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell 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. Cancer Res; 72(19); 5130–40. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received May 16, 2012.
  • Revision received July 23, 2012.
  • Accepted July 25, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Research: 72 (19)
October 2012
Volume 72, Issue 19
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Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay
Tania Fiaschi, Alberto Marini, Elisa Giannoni, Maria Letizia Taddei, Paolo Gandellini, Alina De Donatis, Michele Lanciotti, Sergio Serni, Paolo Cirri and Paola Chiarugi
Cancer Res October 1 2012 (72) (19) 5130-5140; DOI: 10.1158/0008-5472.CAN-12-1949

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Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay
Tania Fiaschi, Alberto Marini, Elisa Giannoni, Maria Letizia Taddei, Paolo Gandellini, Alina De Donatis, Michele Lanciotti, Sergio Serni, Paolo Cirri and Paola Chiarugi
Cancer Res October 1 2012 (72) (19) 5130-5140; DOI: 10.1158/0008-5472.CAN-12-1949
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