The Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Stem Cell Biology & Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Cell Cycle. 2012 Sep 1;11(17):3280-9. doi: 10.4161/cc.21643. Epub 2012 Aug 16.
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.
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中也有所不同。本研究的目的是评估 HIF1α 和 HIF2α 在乳腺癌中的特定细胞区室作用。为此，我们分析了携带组成型激活 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及其在体内促进肿瘤生长的能力。我们观察到，基质细胞中 HIF1α 的激活而非 HIF2α 的激活促进了有氧糖酵解的转变，导致 L-乳酸的产生增加和线粒体活性的丧失。在异种移植模型中，HIF1α 激活的成纤维细胞促进了共注射的 MDA-MB-231 细胞的肿瘤生长，而没有增加血管生成。相反，HIF2α 激活的基质细胞并不有利于肿瘤生长，并且表现为空载体对照。同样，HIF1α 的激活而不是 HIF2α 的激活在 MDA-MB-231 细胞中促进了有氧糖酵解的转变，导致葡萄糖摄取和 L-乳酸的产生增加。相比之下，HIF2α 在癌细胞中的激活增加了 EGFR、Ras 和细胞周期蛋白 D1 的表达，这些都是肿瘤生长和细胞周期进展的已知标志物。在异种移植模型中，HIF1α 在 MDA-MB-231 细胞中的激活作为肿瘤抑制剂，导致肿瘤质量和体积几乎减少了 2 倍。有趣的是，HIF2α 在 MDA-MB-231 细胞中的激活导致肿瘤质量和体积显著增加了约 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表明，HIF2α 肿瘤中的线粒体氧化代谢（OXPHOS）升高。我们得出结论，HIF1α 和 HIF2α 在肿瘤发生中的作用是特定细胞区室的。HIF1α 在基质细胞中作为肿瘤促进剂，但在癌细胞中作为肿瘤抑制剂。相反，HIF2α 是癌细胞中的肿瘤促进剂。从机制上讲，基质细胞中 HIF1α 驱动的有氧糖酵解通过旁分泌产生的营养物质（如 L-乳酸）支持癌细胞的生长，这些营养物质可以“喂养”癌细胞。然而，HIF1α 驱动的癌细胞中的有氧糖酵解抑制肿瘤生长。最后，HIF2α 在癌细胞中的激活诱导了已知的原癌基因分子的表达，并促进了癌细胞的线粒体活性。
