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首页> 外文期刊>Cell cycle >Metabolic reprogramming and two-compartment tumor metabolism: Opposing role(s) of HIF1α and HIF2α in tumor-associated fibroblasts and human breast cancer cells
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Metabolic reprogramming and two-compartment tumor metabolism: Opposing role(s) of HIF1α and HIF2α in tumor-associated fibroblasts and human breast cancer cells

机译：代谢重编程和两室肿瘤代谢：HIF1α和HIF2α在肿瘤相关成纤维细胞和人乳腺癌细胞中的相反作用

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摘要

Hypoxia-inducible factor (HIF) 1α and 2α are transcription factors responsible for the cellular response to hypoxia. The functional roles of HIF1α and HIF2α in cancer are distinct and vary among different tumor types. The aim of this study was to evaluate the compartment-specific role(s) of HIF1α and HIF2α in breast cancer. To this end, immortalized human fibroblasts and MDA-MB-231 breast cancer cells carrying constitutively active HIF1α or HIF2α mutants were analyzed with respect to their metabolic function(s) and ability to promote tumor growth in an in vivo setting. We observed that activation of HIF1α , but not HIF2α, in stromal cells promotes a shift toward aerobic glycolysis, with increased L-lactate production and a loss of mitochondrial activity. In a xenograft model, HIF1α-activated fibroblasts promoted the tumor growth of co-injected MDA-MB-231 cells without an increase in angiogenesis. Conversely, HIF2α-activated stromal cells did not favor tumor growth and behaved as the empty vector controls. Similarly, activation of HIF1α, but not HIF2α, in MDA-MB-231 cells promoted a shift toward aerobic glycolysis, with increased glucose uptake and L-lactate production. In contrast, HIF2α activation in cancer cells increased the expression of EGFR, Ras and cyclin D1, which are known markers of tumor growth and cell cycle progression. In a xenograft model, HIF1α activation in MDA-MB-231 cells acted as a tumor suppressor, resulting in an almost 2-fold reduction in tumor mass and volume. Interestingly, HIF2α activation in MDA-MB-231 cells induced a significant ～2-fold-increase in tumor mass and volume. Analysis of mitochondrial activity in these tumor xenografts using COX (cytochrome C oxidase) staining demonstrated elevated mitochondrial oxidative metabolism (OXPHOS) in HIF2α-tumors. We conclude that the role(s) of HIF1α and HIF2α in tumorigenesis are compartment-specific. HIF1α acts as a tumor promoter in stromal cells but as a tumor suppressor in cancer cells. Conversely, HIF2α is a tumor promoter in cancer cells. Mechanistically, HIF1α-driven aerobic glycolysis in stromal cells supports cancer cell growth via the paracrine production of nutrients (such as L-lactate) that can "feed" cancer cells. However, HIF1α-driven aerobic glycolysis in cancer cells inhibits tumor growth. Finally, HIF2α activation in cancer cells induces the expression of known pro-oncogenic molecules and promotes the mitochondrial activity of cancer cells.
机译：缺氧诱导因子（HIF）1α和2α是负责细胞对缺氧反应的转录因子。 HIF1α和HIF2α在癌症中的功能作用是不同的，并且在不同的肿瘤类型之间有所不同。这项研究的目的是评估HIF1α和HIF2α在乳腺癌中的区室特异性作用。为此，分析了具有组成性活性HIF1α或HIF2α突变体的永生化人成纤维细胞和MDA-MB-231乳腺癌细胞的代谢功能和在体内促进肿瘤生长的能力。我们观察到，基质细胞中HIF1α的激活，而不是HIF2α的激活，促进了向有氧糖酵解的转变，增加了L-乳酸的产生和线粒体活性的丧失。在异种移植模型中，HIF1α激活的成纤维细胞在不增加血管生成的情况下促进了共同注射的MDA-MB-231细胞的肿瘤生长。相反，HIF2α激活的基质细胞不利于肿瘤的生长，并充当空载体对照。同样，MDA-MB-231细胞中的HIF1α激活，而不是HIF2α激活，促进了向有氧糖酵解的转变，增加了葡萄糖的摄取和L-乳酸的产生。相反，癌细胞中的HIF2α激活增加了EGFR，Ras和细胞周期蛋白D1的表达，这是已知的肿瘤生长和细胞周期进程的标志。在异种移植模型中，MDA-MB-231细胞中的HIF1α激活起着抑癌作用，导致肿瘤的体积和体积几乎减少了2倍。有趣的是，MDA-MB-231细胞中的HIF2α激活导致肿瘤的数量和体积显着增加约2倍。使用COX（细胞色素C氧化酶）染色对这些肿瘤异种移植物中的线粒体活性进行分析，结果表明HIF2α肿瘤中的线粒体氧化代谢（OXPHOS）升高。我们得出的结论是，HIF1α和HIF2α在肿瘤发生中的作用是区室特异性的。 HIF1α在基质细胞中充当肿瘤启动子，但在癌细胞中充当肿瘤抑制剂。相反，HIF2α是癌细胞中的肿瘤启动子。从机械上讲，基质细胞中HIF1α驱动的有氧糖酵解通过旁分泌分泌可以“喂食”癌细胞的营养素（例如L-乳酸）来支持癌细胞的生长。但是，HIF1α驱动的癌细胞中有氧糖酵解抑制了肿瘤的生长。最后，癌细胞中的HIF2α激活诱导已知的促癌分子的表达并促进癌细胞的线粒体活性。

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