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首页> 外文期刊>Cell cycle >Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment RAS and NFκB target stromal MCT4
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Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment RAS and NFκB target stromal MCT4

机译：癌基因和炎症改变了肿瘤微环境中RAS和NFκB靶向基质MCT4的宿主能量代谢

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Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFkB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish "metabolic parasites", like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted "antibiotics" to selectively starve cancer cells. Our results provide new support for the "seed and soil" hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.
机译：在这里，我们开发了一个模型系统来评估癌基因对宿主微环境的代谢作用。将匹配的一组“正常”和致癌转化的上皮细胞系与人类成纤维细胞共培养，以确定致癌基因对基质细胞的“旁观者”效应。通过FACS分析测量ROS产生和葡萄糖摄取。此外，平行分析一组代谢蛋白生物标记物（Caveolin-1，MCT1和MCT4）的表达。有趣的是，癌细胞中的癌基因激活足以通过氧化应激诱导与癌症相关的成纤维细胞向糖酵解的代谢重编程。 MCT1 / 4免疫染色提供了氧化癌细胞与糖酵解成纤维细胞之间“代谢共生”的证据。这样，致癌基因驱动了上皮间质“乳酸穿梭”的建立，以促进癌细胞的合成代谢增长。使用两种不同的致癌基因（RAS和NFkB）获得了相似的结果，表明ROS的产生和炎症在肿瘤基质上代谢性聚合，从而驱动糖酵解和MCT4的上调。这些发现使基质MCT4成为新药发现的有吸引力的靶标，因为MCT4是许多致癌刺激物代谢作用的共同终点。因此，多种癌基因刺激肿瘤基质中常见的代谢反应。相反，我们还表明，成纤维细胞可通过减少肿瘤细胞中的ROS生成来保护癌细胞免受致癌应激和衰老。 Ras转化的细胞还能够代谢重编程正常的邻近上皮细胞，这表明癌细胞可以使用成纤维细胞或上皮细胞作为代谢共生的“伴侣”。抗氧化剂N-乙酰半胱氨酸（NAC）选择性地阻止了Ras转化细胞中的线粒体生物发生，但在正常的上皮细胞中却没有。 NAC还阻断了MCT4的基质诱导，表明NAC有效地充当了“ MCT4抑制剂”。综上，我们的数据为实现更有效的抗癌治疗提供了新的策略。我们得出结论，癌基因使癌细胞像外来生物（细菌，真菌，病毒）一样表现为自私的“代谢寄生虫”。因此，我们应该考虑使用新型的代谢靶向“抗生素”来选择性地使癌细胞饿死，从而将癌症像传染病一样对待。我们的结果为“种子和土壤”假说提供了新的支持，这一假说由英国外科医生Stephen Paget于1889年首次提出。

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