Hypoxia-Induced Secretion of TGF-β1 in Mesenchymal Stem Cell Promotes Breast Cancer Cell Progression
Hypoxia-Induced Secretion of TGF-β1 in Mesenchymal Stem Cell Promotes Breast Cancer Cell Progression
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DOI：
10.3727/096368912x657954
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发表时间：
2013-01-01
影响因子：
3.3
通讯作者：
Lee, Oscar K.
中科院分区：
文献类型：
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作者：
Hung, Shun-Pei;Yang, Muh-Hwa;Lee, Oscar K.
在实体瘤中，氧气和营养供应减少在中心区域产生缺氧微环境。这种低氧条件诱导局部区域正常细胞和癌细胞的分子反应，包括血管生成、代谢变化和转移。此外，据报道，包括间充质干细胞（MSC）在内的其他细胞被募集到实体瘤的缺氧区域。在我们以前的研究中，我们发现低氧条件诱导MSC分泌生长因子和细胞因子，在这里，我们证明了低氧条件下MSC分泌转化生长因子-β 1（TGF-β 1）的升高促进乳腺癌细胞的生长，运动和侵袭能力。结果表明，TGF-β 1启动子活性受缺氧调节，主要的缺氧调节元件位于TGF-β 1启动子区前1030 - 666 bp之间。在ChIP实验中，结果显示HIF-1与TGF-β 1启动子的缺氧反应元件（HRE）结合。总之，结果表明，缺氧微环境可以通过MSC的旁分泌效应通过驱动其TGF-β 1基因表达和分泌来增强癌细胞生长。因此，当考虑在细胞移植到患者中用于治疗目的之前对MSC进行缺氧预处理时，必须格外小心，特别是在易受肿瘤生长影响的患者中。
In solid tumors, a decreased oxygen and nutrient supply creates a hypoxic microenvironment in the central region. This hypoxic condition induces molecular responses of normal and cancer cells in the local area, including angiogenesis, metabolic changes, and metastasis. In addition, other cells including mesenchymal stem cells (MSCs) have been reported to be recruited into the hypoxic area of solid tumors. In our previous study, we found that hypoxic condition induces the secretion of growth factors and cytokines in MSCs, and here we demonstrate that elevated secretion of transforming growth factor-beta 1 (TGF-beta 1) by MSCs under hypoxia promotes the growth, motility, and invasive ability of breast cancer cells. It was found that TGF-beta 1 promoter activity was regulated by hypoxia, and the major hypoxia-regulated element was located between bp 1030 to 666 in front of the TGF-beta 1 promoter region. In ChIP assay, the results revealed that HIF-1 was bound to the hypoxia response element (HRE) of TGF-beta 1 promoter. Collectively, the results indicate that hypoxia microenvironment can enhance cancer cell growth through the paracrine effects of the MSCs by driving their TGF-beta 1 gene expression and secretion. Therefore, extra caution has to be exercised when considering hypoxia pretreatment of MSCs before cell transplantation into patients for therapeutic purposes, particularly in patients susceptible to tumor growth.