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首页> 外文期刊>Cell cycle >The reverse Warburg effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.
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The reverse Warburg effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts.

机译：反向的Warburg效应：糖酵解抑制剂可预防Caveolin-1缺陷型癌症相关成纤维细胞的促肿瘤作用。

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We and others have previously identified a loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts (CAFs) as a powerful single independent predictor of breast cancer patient tumor recurrence, metastasis, tamoxifen-resistance and poor clinical outcome. However, it remains unknown how loss of stromal Cav-1 mediates these effects clinically. To mechanistically address this issue, we have now generated a novel human tumor xenograft model. In this two-component system, nude mice are co-injected with (i) human breast cancer cells (MDA-MB-231), and (ii) stromal fibroblasts (wild-type (WT) versus Cav-1 (-/-) deficient). This allowed us to directly evaluate the effects of a Cav-1 deficiency solely in the tumor stromal compartment. Here, we show that Cav-1-deficient stromal fibroblasts are sufficient to promote both tumor growth and angiogenesis, and to recruit Cav-1 (+) micro-vascular cells. Proteomic analysis of Cav-1-deficient stromal fibroblasts indicates that these cells upregulate the expression of glycolytic enzymes, a hallmark of aerobic glycolysis (the Warburg effect). Thus, Cav-1-deficient stromal fibroblasts may contribute towards tumor growth and angiogenesis, by providing energy-rich metabolites in a paracrine fashion. We have previously termed this new idea the "Reverse Warburg Effect". In direct support of this notion, treatment of this xenograft model with glycolysis inhibitors functionally blocks the positive effects of Cav-1-deficient stromal fibroblasts on breast cancer tumor growth. Thus, pharmacologically-induced metabolic restriction (via treatment with glycolysis inhibitors) may be a promising new therapeutic strategy for breast cancer patients that lack stromal Cav-1 expression. We also identify the stromal expression of PKM2 and LDH-B as new candidate biomarkers for the "Reverse Warburg Effect" or "Stromal-Epithelial Metabolic Coupling" in human breast cancers.
机译：我们和其他人先前已经确定，与癌症相关的成纤维细胞（CAF）中基质小窝蛋白1（Cav-1）的丧失是乳腺癌患者肿瘤复发，转移，他莫昔芬耐药性和不良临床预后的强有力的独立预测因子。但是，尚不清楚间质Cav-1的丧失如何在临床上介导这些作用。为了机械地解决这个问题，我们现在生成了一种新型的人类肿瘤异种移植模型。在此两成分系统中，将裸鼠与（i）人乳腺癌细胞（MDA-MB-231）和（ii）基质成纤维细胞（野生型（WT）与Cav-1（-/- ）不足）。这使我们能够直接在肿瘤基质区隔中直接评估Cav-1缺乏症的影响。在这里，我们表明缺乏Cav-1的基质成纤维细胞足以促进肿瘤生长和血管生成，并募集Cav-1（+）微血管细胞。缺乏Cav-1的基质成纤维细胞的蛋白质组学分析表明，这些细胞上调了糖酵解酶的表达，这是有氧糖酵解的标志（Warburg效应）。因此，缺乏Cav-1的基质成纤维细胞可能通过旁分泌方式提供能量丰富的代谢产物，从而促进肿瘤的生长和血管生成。我们以前将这个新想法称为“反向Warburg效应”。在这一观点的直接支持下，用糖酵解抑制剂治疗该异种移植模型在功能上阻断了Cav-1缺乏型基质成纤维细胞对乳腺癌肿瘤生长的积极作用。因此，药理学诱导的代谢限制（通过糖酵解抑制剂治疗）可能是缺乏基质Cav-1表达的乳腺癌患者的有希望的新治疗策略。我们还确定了人类乳腺癌中PKM2和LDH-B的基质表达作为“逆向Warburg效应”或“ Stromal-上皮代谢耦合”的新候选生物标志物。

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