Mitochondrial metabolism in cancer metastasis Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue
Mitochondrial metabolism in cancer metastasis Visualizing tumor cell mitochondria and the "reverse Warburg effect" in positive lymph node tissue
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DOI：
10.4161/cc.19841
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发表时间：
2012-04-01
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：
Sotgia, Federica;Whitaker-Menezes, Diana;Lisanti, Michael P.
我们最近提出了一个新的两室模型来理解肿瘤代谢中的Warburg效应。在这个模型中，糖酵解基质细胞产生线粒体燃料(L-乳酸和酮体)，然后转移到氧化上皮癌细胞，驱动OXPHOS和线粒体代谢。因此，间质分解代谢通过能量转移促进合成代谢肿瘤的生长。我们将这种新的癌症模式命名为“逆瓦堡效应”，因为基质细胞进行有氧糖酵解，而不是肿瘤细胞。为了评估这一机制是否也适用于癌细胞转移，我们通过使用一系列代谢蛋白标记物来分析乳腺癌淋巴转移的生物能量状态。为此，我们使用MCT4来鉴定糖酵解细胞。同样，我们使用TOMM20和COX染色分别作为线粒体质量和OXPHOS活性的标记。与“逆向Warburg效应”一致的是，我们的结果表明，转移性乳腺癌细胞放大了氧化线粒体代谢(OXPHOS)，邻近的基质细胞是糖酵解的，缺乏可检测到的线粒体。糖酵解基质细胞包括癌症相关的成纤维细胞、脂肪细胞和炎症细胞。糖酵解(MCT4)和氧化(TOMM20或COX)标记物的双标记实验直接表明，在原发肿瘤及其转移中，至少有两个不同的代谢室并存。由于癌症相关的免疫细胞出现糖酵解，这一观察也可以解释炎症是如何通过给癌细胞中的线粒体新陈代谢“供养”而字面上“助长”肿瘤的进展和转移的。最后，很少观察到MCT4(+)和TOMM20(-)“糖酵解”癌细胞，这表明传统的“Warburg效应”并不经常出现在癌症阳性的淋巴结转移中。
We have recently proposed a new two-compartment model for understanding the Warburg effect in tumor metabolism. In this model, glycolytic stromal cells produce mitochondrial fuels (L-lactate and ketone bodies) that are then transferred to oxidative epithelial cancer cells, driving OXPHOS and mitochondrial metabolism. Thus, stromal catabolism fuels anabolic tumor growth via energy transfer. We have termed this new cancer paradigm the "reverse Warburg effect," because stromal cells undergo aerobic glycolysis, rather than tumor cells. To assess whether this mechanism also applies during cancer cell metastasis, we analyzed the bioenergetic status of breast cancer lymph node metastases, by employing a series of metabolic protein markers. For this purpose, we used MCT4 to identify glycolytic cells. Similarly, we used TOMM20 and COX staining as markers of mitochondrial mass and OXPHOS activity, respectively. Consistent with the " reverse Warburg effect," our results indicate that metastatic breast cancer cells amplify oxidative mitochondrial metabolism (OXPHOS) and that adjacent stromal cells are glycolytic and lack detectable mitochondria. Glycolytic stromal cells included cancer-associated fibroblasts, adipocytes and inflammatory cells. Double labeling experiments with glycolytic (MCT4) and oxidative (TOMM20 or COX) markers directly shows that at least two different metabolic compartments co-exist, side-by-side, within primary tumors and their metastases. Since cancer-associated immune cells appeared glycolytic, this observation may also explain how inflammation literally "fuels" tumor progression and metastatic dissemination, by "feeding" mitochondrial metabolism in cancer cells. Finally, MCT4(+) and TOMM20(-) "glycolytic" cancer cells were rarely observed, indicating that the conventional "Warburg effect" does not frequently occur in cancer-positive lymph node metastases.