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, Paola Chiarugi

Research output: Contribution to journalArticle

202 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5130-5140
Number of pages11
JournalCancer Research
Volume72
Issue number19
DOIs
Publication statusPublished - Oct 1 2012

Fingerprint

Lactic Acid
Prostatic Neoplasms
Neoplasms
Hypoxia-Inducible Factor 1
Epithelial-Mesenchymal Transition
Stromal Cells
Glucose
Prostate
Monocarboxylic Acid Transporters
Fibroblasts
Facilitative Glucose Transport Proteins
Oxidation-Reduction
Hyperplasia
Cell Survival
Oxidative Stress
Stem Cells
Phenotype
Gene Expression
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fiaschi, T., Marini, A., Giannoni, E., Taddei, M. L., Gandellini, P., De Donatis, A., ... Chiarugi, P. (2012). Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Research, 72(19), 5130-5140. https://doi.org/10.1158/0008-5472.CAN-12-1949

Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. / Fiaschi, Tania; Marini, Alberto; Giannoni, Elisa; Taddei, Maria Letizia; Gandellini, Paolo; De Donatis, Alina; Lanciotti, Michele; Serni, Sergio; Cirri, Paolo; Chiarugi, Paola.

In: Cancer Research, Vol. 72, No. 19, 01.10.2012, p. 5130-5140.

Research output: Contribution to journalArticle

Fiaschi, T, Marini, A, Giannoni, E, Taddei, ML, Gandellini, P, De Donatis, A, Lanciotti, M, Serni, S, Cirri, P & Chiarugi, P 2012, 'Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay', Cancer Research, vol. 72, no. 19, pp. 5130-5140. https://doi.org/10.1158/0008-5472.CAN-12-1949
Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Research. 2012 Oct 1;72(19):5130-5140. https://doi.org/10.1158/0008-5472.CAN-12-1949
Fiaschi, Tania ; Marini, Alberto ; Giannoni, Elisa ; Taddei, Maria Letizia ; Gandellini, Paolo ; De Donatis, Alina ; Lanciotti, Michele ; Serni, Sergio ; Cirri, Paolo ; Chiarugi, Paola. / Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. In: Cancer Research. 2012 ; Vol. 72, No. 19. pp. 5130-5140.
@article{03d66b62f4a24a91b887065b40b96240,
title = "Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay",
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.",
author = "Tania Fiaschi and Alberto Marini and Elisa Giannoni and Taddei, {Maria Letizia} and Paolo Gandellini and {De Donatis}, Alina and Michele Lanciotti and Sergio Serni and Paolo Cirri and Paola Chiarugi",
year = "2012",
month = "10",
day = "1",
doi = "10.1158/0008-5472.CAN-12-1949",
language = "English",
volume = "72",
pages = "5130--5140",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "19",

}

TY - JOUR

T1 - Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay

AU - Fiaschi, Tania

AU - Marini, Alberto

AU - Giannoni, Elisa

AU - Taddei, Maria Letizia

AU - Gandellini, Paolo

AU - De Donatis, Alina

AU - Lanciotti, Michele

AU - Serni, Sergio

AU - Cirri, Paolo

AU - Chiarugi, Paola

PY - 2012/10/1

Y1 - 2012/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867112200&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867112200&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-12-1949

DO - 10.1158/0008-5472.CAN-12-1949

M3 - Article

VL - 72

SP - 5130

EP - 5140

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 19

ER -