The reverse Warburg effect Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma
The reverse Warburg effect Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma
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DOI：
10.4161/cc.8.23.10238
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发表时间：
2009-12-01
期刊：
影响因子：
4.3
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
--
作者：
Pavlides, Stephanos;Whitaker-Menezes, Diana;Lisanti, Michael P.
在这里，我们提出了一个新的模型来理解肿瘤代谢中的Warburg效应。我们的假设是，上皮性癌细胞在邻近的间质成纤维细胞中诱导了Warburg效应(有氧糖酵解)。这些与癌症相关的成纤维细胞，然后经历肌成纤维细胞分化，并分泌乳酸和丙酮酸(有氧糖酵解产生的能量代谢物)。然后，上皮性癌细胞可以摄取这些能量丰富的代谢物，并在线粒体TCA循环中使用它们，从而促进有效的能量产生(通过氧化磷酸化产生ATP)，从而产生更高的增殖能力。在这一肿瘤发生的替代模型中，上皮性癌细胞指示正常的间质转化为伤口愈合的间质，为促进肿瘤生长和血管生成提供必要的能量丰富的微环境。本质上，成纤维细胞肿瘤间质将以一种宿主-寄生虫的关系直接喂养上皮性癌细胞。我们将这一新想法称为“逆瓦堡效应”。在这种情况下，上皮性肿瘤细胞“破坏”正常的间质，把它变成生产能量丰富的代谢物的工厂。这一替代模型仍然与Warburg最初的观察一致，即肿瘤显示出代谢向有氧糖酵解的转变。为了支持这一观点，对一种新的癌症相关成纤维细胞模型(小窝蛋白-1(Cav-1)缺陷的基质细胞)的无偏见蛋白质组学分析和转录图谱显示，在常氧条件下，(1)肌成纤维细胞标志物和(2)糖酵解酶均上调。我们验证了这些蛋白在缺乏间质Cav-1的人乳腺癌组织的成纤维细胞间质中的表达。重要的是，人类乳腺癌间质Cav-1的缺失与肿瘤复发、转移和不良的临床预后有关。因此，基质Cav-1的缺失可能是“反向Warburg效应”的一个生物标志物，解释了其强大的预测价值。
Here, we propose a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce the Warburg effect (aerobic glycolysis) in neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate and pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial cancer cells could then take up these energy-rich metabolites and use them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), resulting in a higher proliferative capacity. In this alternative model of tumorigenesis, the epithelial cancer cells instruct the normal stroma to transform into a wound-healing stroma, providing the necessary energy-rich micro-environment for facilitating tumor growth and angiogenesis. In essence, the fibroblastic tumor stroma would directly feed the epithelial cancer cells, in a type of host-parasite relationship. We have termed this new idea the "Reverse Warburg Effect." In this scenario, the epithelial tumor cells "corrupt" the normal stroma, turning it into a factory for the production of energy-rich metabolites. This alternative model is still consistent with Warburg's original observation that tumors show a metabolic shift towards aerobic glycolysis. In support of this idea, unbiased proteomic analysis and transcriptional profiling of a new model of cancer-associated fibroblasts (caveolin-1 (Cav-1) deficient stromal cells), shows the upregulation of both (1) myo-fibroblast markers and (2) glycolytic enzymes, under normoxic conditions. We validated the expression of these proteins in the fibroblastic stroma of human breast cancer tissues that lack stromal Cav-1. Importantly, a loss of stromal Cav-1 in human breast cancers is associated with tumor recurrence, metastasis, and poor clinical outcome. Thus, an absence of stromal Cav-1 may be a biomarker for the "Reverse Warburg Effect," explaining its powerful predictive value.