Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation.
Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation.
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DOI：
10.18632/oncotarget.11712
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Podgorski I
中科院分区：
文献类型：
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作者：
Diedrich JD;Rajagurubandara E;Herroon MK;Mahapatra G;Hüttemann M;Podgorski I
代谢适应越来越被认为是肿瘤进展的关键因素，但其在转移性骨病中的作用尚不清楚。骨是富含脂肪细胞的器官，也是前列腺癌转移的主要部位。骨髓脂肪细胞是代谢活跃的细胞，能够通过脂肪分解和脂质转移来塑造肿瘤代谢。在这项研究中，我们使用体外和体内骨髓脂肪模型，证明骨髓脂肪细胞促进转移性前列腺癌细胞的Warburg表型。我们发现，在暴露于脂肪细胞的肿瘤细胞中，糖酵解酶的表达增加，乳酸生成增加，线粒体氧化磷酸化减少，这需要两种细胞类型之间的旁分泌信号。我们还揭示前列腺癌细胞能够诱导脂肪细胞脂解作为一种假定的维持机制。我们提供的证据表明，脂肪细胞通过不依赖氧的HIF-1α激活机制驱动肿瘤细胞的代谢重编程，该机制可以通过HIF-1α下调来逆转。重要的是，我们还证明，在暴露于脂肪细胞的肿瘤细胞中观察到的代谢特征与转移性疾病患者中观察到的表达模式相似。总之，我们的数据为骨髓脂肪细胞和骨肿瘤细胞之间的功能关系提供了证据，这可能影响肿瘤在转移生态位内的生长和存活。
Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche.