间质细胞
癌细胞
前列腺癌
重编程
过剩1
癌症研究
生物
葡萄糖转运蛋白
瓦博格效应
上皮-间质转换
肿瘤进展
癌症
葡萄糖摄取
细胞生物学
肿瘤微环境
细胞
厌氧糖酵解
化学
转移
内分泌学
生物化学
肿瘤细胞
胰岛素
遗传学
作者
Tania Fiaschi,Alberto Marini,Elisa Giannoni,Maria Letizia Taddei,Paolo Gandellini,Alina De Donatis,Michele Lanciotti,Sergio Serni,Paolo Cirri,Paola Chiarugi
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2012-08-01
卷期号:72 (19): 5130-5140
被引量:495
标识
DOI:10.1158/0008-5472.can-12-1949
摘要
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.
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