Ketones and lactate "fuel" tumor growth and metastasis Evidence that epithelial cancer cells use oxidative mitochondrial metabolism
Ketones and lactate "fuel" tumor growth and metastasis Evidence that epithelial cancer cells use oxidative mitochondrial metabolism
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DOI：
10.4161/cc.9.17.12731
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发表时间：
2010-09-01
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：
Bonuccelli, Gloria;Tsirigos, Aristotelis;Lisanti, Michael P.
在此之前，我们提出了一个新的模型来理解肿瘤代谢中的“瓦尔堡效应”。在该方案中，癌症相关的成纤维细胞经历有氧糖酵解，然后将所产生的富含能量的代谢物转移到上皮癌细胞，在那里它们进入TCA循环，通过氧化磷酸化产生高ATP。我们把这种新的范式称为“反向瓦尔堡效应”。“在这里，我们使用MDA-MB-231乳腺癌异种移植物作为模型系统，直接评估有氧糖酵解的终产物（3-羟基丁酸盐和L-乳酸盐）是否可以刺激肿瘤生长和转移。更具体地说，我们表明，3-羟基丁酸酯（酮体）的管理增加肿瘤生长的2.5倍，没有任何可测量的增加肿瘤血管化/血管生成。3-羟基丁酸盐和L-乳酸盐都起化学引诱剂的作用，刺激上皮癌细胞的迁移。虽然L-乳酸盐没有增加原发性肿瘤的生长，但它刺激了肺转移瘤的形成，增加了10倍。因此，我们得出结论，酮和乳酸盐促进肿瘤生长和转移，提供功能证据支持“反向瓦尔堡效应”。“此外，我们讨论了在癌症患者中使用含乳酸盐的静脉注射溶液（如乳酸林格氏溶液或哈特曼溶液）可能是不明智的，因为L-乳酸盐具有显著的促进转移的特性。此外，我们提供了证据的氧化线粒体代谢和TCA循环在体内的人乳腺癌细胞的上调，通过信息学分析现有的原始转录谱的上皮乳腺癌细胞和相邻的基质细胞。最后，我们的研究结果可以解释为什么糖尿病患者的癌症发病率增加，这是由于酮的产生增加，以及脂肪组织中自噬/线粒体自噬的趋势。
Previously, we proposed a new model for understanding the "Warburg effect" in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm "The Reverse Warburg Effect." Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by similar to 2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells. Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by similar to 10-fold. Thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the "Reverse Warburg Effect." Moreover, we discuss the possibility that it may be unwise to use lactate-containing i.v. solutions (such as Lactated Ringer's or Hartmann's solution) in cancer patients, given the dramatic metastasis-promoting properties of L-lactate. Also, we provide evidence for the up-regulation of oxidative mitochondrial metabolism and the TCA cycle in human breast cancer cells in vivo, via an informatics analysis of the existing raw transcriptional profiles of epithelial breast cancer cells and adjacent stromal cells. Lastly, our findings may explain why diabetic patients have an increased incidence of cancer, due to increased ketone production, and a tendency towards autophagy/mitophagy in their adipose tissue.