Department of Stem Cell Biology & Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
Cell Cycle. 2009 Dec;8(23):3984-4001. doi: 10.4161/cc.8.23.10238. Epub 2009 Dec 5.
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.
在这里，我们提出了一个新的模型来理解肿瘤代谢中的瓦博格效应。我们的假设是上皮癌细胞诱导邻近基质成纤维细胞发生瓦博格效应（有氧糖酵解）。这些癌相关成纤维细胞随后发生肌成纤维细胞分化，并分泌乳酸盐和丙酮酸（有氧糖酵解产生的能量代谢物）。上皮癌细胞可以摄取这些富含能量的代谢物，并将其用于线粒体三羧酸（TCA）循环，从而促进有效的能量产生（通过氧化磷酸化生成 ATP），从而提高增殖能力。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创伤愈合基质，为促进肿瘤生长和血管生成提供必要的富含能量的微环境。从本质上讲，成纤维性肿瘤基质将直接为上皮癌细胞提供营养，形成一种宿主-寄生虫关系。我们将这个新的想法称为“反向瓦博格效应”。在这种情况下，上皮肿瘤细胞“腐化”正常基质，将其转化为生产富含能量代谢物的工厂。这个替代模型仍然符合瓦博格最初的观察结果，即肿瘤表现出向有氧糖酵解的代谢转变。为了支持这个想法，对一种新的癌相关成纤维细胞模型（窖蛋白-1（Cav-1）缺陷的基质细胞）进行无偏蛋白质组学分析和转录谱分析，结果显示在常氧条件下，（1）肌成纤维细胞标志物和（2）糖酵解酶的表达均上调。我们在缺乏基质 Cav-1 的人类乳腺癌组织的成纤维性基质中验证了这些蛋白质的表达。重要的是，人类乳腺癌中基质 Cav-1 的缺失与肿瘤复发、转移和不良临床结局相关。因此，基质 Cav-1 的缺失可能是“反向瓦博格效应”的标志物，解释了其强大的预测价值。
