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.

• Authors: Tania Fiaschi, Alberto Marini, Elisa Giannoni, Maria Letizia Taddei, Paolo Gandellini, Alina De Donatis, Michele Lanciotti, Sergio Serni, Paolo Cirri, Paola Chiarugi
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 19 Pg. 5130-40 (Oct 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22850421 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Glucose Transporter Type 1
• Hypoxia-Inducible Factor 1
• Monocarboxylic Acid Transporters
• Muscle Proteins
• SLC16A4 protein, human
• SLC2A1 protein, human
• Lactic Acid
• SIRT3 protein, human
• Sirtuin 3
• Glucose

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Cells, Cultured
• Fibroblasts (metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Glucose (metabolism)
• Glucose Transporter Type 1 (genetics, metabolism)
• Glycolysis
• Humans
• Hypoxia-Inducible Factor 1 (genetics, metabolism)
• Lactic Acid (metabolism)
• Male
• Mice
• Mice, SCID
• Mitochondria (metabolism)
• Models, Biological
• Monocarboxylic Acid Transporters (genetics, metabolism)
• Muscle Proteins (genetics, metabolism)
• Neoplasms, Experimental (genetics, metabolism, pathology)
• Oxidative Stress
• Prostatic Neoplasms (genetics, metabolism, pathology)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Sirtuin 3 (genetics, metabolism)
• Transplantation, Heterologous