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首页> 外文期刊>Cell cycle >HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis.
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HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis.

机译：HIF1-alpha在癌症相关的成纤维细胞中起着肿瘤促进剂的作用，在乳腺癌细胞中起着抑癌剂的作用：自噬可驱动特定部位的肿瘤发生。

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Our recent studies have mechanistically implicated a loss of stromal Cav-1 expression and HIF1-alpha-activation in driving the cancer-associated fibroblast phenotype, through the paracrine production of nutrients via autophagy and aerobic glycolysis. However, it remains unknown if HIF1a-activation is sufficient to confer the cancer-associated fibroblast phenotype. To test this hypothesis directly, we stably-expressed activated HIF1a in fibroblasts and then examined their ability to promote tumor growth using a xenograft model employing human breast cancer cells (MDA-MB-231). Fibroblasts harboring activated HIF1a showed a dramatic reduction in Cav-1 levels and a shift towards aerobic glycolysis, as evidenced by a loss of mitochondrial activity, and an increase in lactate production. Activated HIF1a also induced BNIP3 and BNIP3L expression, markers for the autophagic destruction of mitochondria. Most importantly, fibroblasts expressing activated HIF1a increased tumor mass by approximately 2-fold and tumor volume by approximately 3-fold, without a significant increase in tumor angiogenesis. In this context, HIF1a also induced an increase in the lymph node metastasis of cancer cells. Similar results were obtained by driving NFkappaB activation in fibroblasts, another inducer of autophagy. Thus, activated HIF1a is sufficient to functionally confer the cancer-associated fibroblast phenotype. It is also known that HIF1a expression is required for the induction of autophagy in cancer cells. As such, we next directly expressed activated HIF1a in MDA-MB-231 cells and assessed its effect on tumor growth via xenograft analysis. Surprisingly, activated HIF1a in cancer cells dramatically suppressed tumor growth, resulting in a 2-fold reduction in tumor mass and a 3-fold reduction in tumor volume. We conclude that HIF1a activation in different cell types can either promote or repress tumorigenesis. Based on these studies, we suggest that autophagy in cancer-associated fibroblasts promotes tumor growth via the paracrine production of recycled nutrients, which can directly "feed" cancer cells. Conversely, autophagy in cancer cells represses tumor growth via their self-digestion oncogenes and tumor-suppressors may be compartment and cell-type specific, and are not necessarily an intrinsic property of the molecule itself. As such, other classic determine their compartment specific effects on tumor growth and metastasis. Lastly, our results provide direct experimental support for the recently proposed Autophagic Tumor Stroma Model of Cancer
机译：我们最近的研究从机制上暗示了通过自噬和有氧糖酵解通过旁分泌产生营养来驱动癌症相关的成纤维细胞表型时，基质Cav-1表达和HIF1-α的丧失。然而，仍不清楚是否HIF1a激活足以赋予与癌症相关的成纤维细胞表型。为了直接检验该假设，我们在成纤维细胞中稳定表达了活化的HIF1a，然后使用人乳腺癌细胞（MDA-MB-231）的异种移植模型检查了它们促进肿瘤生长的能力。线粒体活性的丧失和乳酸产量的增加证明了具有活化的HIF1a的成纤维细胞的Cav-1水平显着降低，并向有氧糖酵解转变。活化的HIF1a还诱导BNIP3和BNIP3L表达，这是线粒体自噬破坏的标志。最重要的是，表达活化的HIF1a的成纤维细胞将肿瘤量增加了约2倍，将肿瘤体积增加了约3倍，而肿瘤血管生成没有明显增加。在这种情况下，HIF1a还诱导癌细胞淋巴结转移的增加。通过驱动成纤维细胞中的NFkappaB激活（自噬的另一种诱导剂）获得了相似的结果。因此，活化的HIF1a足以在功能上赋予与癌症相关的成纤维细胞表型。还已知在癌细胞中诱导自噬需要HIF1a表达。因此，我们接下来直接在MDA-MB-231细胞中表达活化的HIF1a，并通过异种移植分析评估其对肿瘤生长的影响。出乎意料的是，癌细胞中活化的HIF1a显着抑制了肿瘤的生长，导致肿瘤量减少了2倍，肿瘤体积减少了3倍。我们得出的结论是，不同细胞类型中的HIF1a激活可以促进或抑制肿瘤发生。基于这些研究，我们建议癌症相关的成纤维细胞中的自噬通过旁分泌产生可循环利用的营养物质来促进肿瘤生长，这可以直接“喂食”癌细胞。相反，癌细胞中的自噬通过自身消化的癌基因抑制肿瘤的生长，而肿瘤抑制因子可能是区室和细胞类型特异性的，不一定是分子本身的固有特性。因此，其他经典方法决定了它们对肿瘤生长和转移的区室特异性作用。最后，我们的结果为最近提出的癌症自噬肿瘤基质模型提供了直接的实验支持。

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