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
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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DOI：
10.4161/cc.9.17.12908
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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：
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作者：
Chiavarina, Barbara;Whitaker-Menezes, Diana;Lisanti, Michael P.
我们最近的研究已经从机制上暗示了基质Cav-1表达和HIF 1-α激活的损失，通过自噬和有氧糖酵解旁分泌产生营养物质来驱动癌症相关的成纤维细胞表型。然而，它仍然是未知的，如果HIF-1a激活是足以赋予癌症相关的成纤维细胞表型。为了直接验证这一假设，我们在成纤维细胞中稳定表达活化的HIF 1a，然后使用采用人乳腺癌细胞（MDA-MB-231）的异种移植模型检查其促进肿瘤生长的能力。携带活化HIF 1a的成纤维细胞显示Cav-1水平的急剧降低和向有氧糖酵解的转变，如线粒体活性的丧失和乳酸产生的增加所证明的。活化的HIF 1a还诱导BNIP 3和BNIP 3L表达，这是线粒体自噬破坏的标志物。最重要的是，表达活化HIF 1a的成纤维细胞使肿瘤质量增加了2倍，肿瘤体积增加了3倍，而肿瘤血管生成没有显著增加。在这种情况下，HIF 1a还诱导癌细胞的淋巴结转移增加。通过驱动成纤维细胞中的NF κ B活化（另一种自噬诱导剂）获得了类似的结果。因此，活化的HIF 1a足以在功能上赋予癌症相关的成纤维细胞表型。还已知HIF 1a表达是诱导癌细胞自噬所必需的。因此，我们接下来在MDA-MB-231细胞中直接表达活化的HIF 1a，并通过异种移植物分析评估其对肿瘤生长的影响。令人惊讶的是，癌细胞中激活的HIF 1a显著抑制肿瘤生长，导致肿瘤质量减少2倍，肿瘤体积减少3倍。我们的结论是，HIF 1a在不同类型的细胞激活可以促进或抑制肿瘤发生。基于这些研究，我们认为癌症相关成纤维细胞中的自噬通过旁分泌产生可直接“喂养”癌细胞的再循环营养物质来促进肿瘤生长。相反，癌细胞中的自噬通过其“自我消化”抑制肿瘤生长。因此，我们应该考虑到，各种已知的癌基因和肿瘤抑制因子的活性可能是区室和细胞类型特异性的，而不一定是分子本身的内在特性。因此，其他“经典”癌基因和肿瘤抑制基因将不得不重新评估，以确定其对肿瘤生长和转移的隔室特异性作用。最后，我们的研究结果为最近提出的“肿瘤自噬基质模型”提供了直接的实验支持。
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 similar to 2-fold and tumor volume by similar to 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 NF kappa B 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". Thus, we should consider that the activities of various known 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" oncogenes and tumor suppressors will have to be re-evaluated to 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".