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首页> 外文期刊>Cell cycle >The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.
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The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma.

机译：反向的Warburg效应：与癌症相关的成纤维细胞和肿瘤基质中的有氧糖酵解。

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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.
机译：在这里，我们提出了一种新模型，用于了解Warburg在肿瘤代谢中的作用。我们的假设是，上皮癌细胞在邻近的基质成纤维细胞中诱导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产物）。然后，上皮癌细胞可以吸收这些能量丰富的代谢物，并将其用于线粒体TCA循环，从而促进有效的能量产生（通过氧化磷酸化产生ATP），从而具有更高的增殖能力。在这种肿瘤发生的替代模型中，上皮癌细胞指示正常基质转化为伤口愈合基质，从而提供必要的能量丰富的微环境，以促进肿瘤的生长和血管生成。本质上，成纤维细胞肿瘤基质将以一种宿主-寄生虫的关系直接喂食上皮癌细胞。我们称这种新想法为“反向Warburg效应”。在这种情况下，上皮肿瘤细胞会“破坏”正常基质，将其变成生产高能代谢产物的工厂。这种替代模型仍与Warburg最初的观察结果一致，即肿瘤显示代谢向有氧糖酵解转变。为了支持这一想法，对与癌症相关的成纤维细胞（caveolin-1（Cav-1）缺陷基质细胞）的新模型进行了无偏见的蛋白质组学分析和转录谱分析，显示了（1）肌成纤维细胞标志物和（2 ）在常氧条件下的糖酵解酶。我们验证了这些蛋白在缺乏基质Cav-1的人乳腺癌组织的成纤维细胞基质中的表达。重要的是，人类乳腺癌中基质Cav-1的缺失与肿瘤的复发，转移和不良的临床预后有关。因此，不存在基质Cav-1可能是“逆向Warburg效应”的生物标记，解释了其强大的预测价值。

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