Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay
Reciprocal Metabolic Reprogramming through Lactate Shuttle Coordinately Influences Tumor-Stroma Interplay
复制标题
DOI：
10.1158/0008-5472.can-12-1949
复制
发表时间：
2012-10-01
期刊：
影响因子：
11.2
通讯作者：
Chiarugi, Paola
中科院分区：
文献类型：
--
作者：
Fiaschi, Tania;Marini, Alberto;Chiarugi, Paola
癌症相关成纤维细胞（CAF）通过促进癌细胞经历上皮-间充质转化（EMT）的能力以及通过增强干细胞性状和转移性传播参与肿瘤进展。在这里，我们表明CAFs和前列腺癌细胞之间的相互作用超出了EMT的参与，包括相互代谢重编程。体外培养的CAFs或从良性前列腺增生获得的人前列腺成纤维细胞的基因表达分析揭示CAFs经历瓦尔堡代谢和线粒体氧化应激。这种朝向瓦尔堡表型的代谢重编程是由于与前列腺癌细胞接触而发生的。细胞间接触激活基质成纤维细胞，触发葡萄糖转运蛋白GLUT 1表达增加，乳酸产生，并通过从头表达的单羧酸转运蛋白4（MCT 4）挤出乳酸。相反，前列腺癌细胞在与CAF接触后，被重新编程为有氧代谢，GLUT 1表达减少，乳酸转运蛋白MCT 1的乳酸上传增加。基质细胞和癌细胞的代谢重编程都受到低氧诱导因子1（HIF 1）的严格控制，HIF 1在常氧条件下驱动氧化还原和SIRT 3依赖性HIF 1的稳定。前列腺癌细胞逐渐变得不依赖于葡萄糖消耗，同时发展出对乳酸上传的依赖，以驱动合成代谢途径，从而促进细胞生长。一致的是，药物抑制MCT 1介导的乳酸上传显着影响前列腺癌细胞的存活和肿瘤生长。因此，癌细胞将瓦尔堡代谢分配给其受损的CAF，利用其副产物在低葡萄糖环境中生长，与基质细胞共生地适应葡萄糖可用性。Cancer Res; 72（19）; 5130-40.（C）2012年AACR。
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. (C)2012 AACR.