Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan ; Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan ; The Institute for Translational Medicine, Taipei Medical University, Taipei, Taiwan.
PLoS One. 2013 Aug 19;8(8):e71637. doi: 10.1371/journal.pone.0071637. eCollection 2013.
Bone marrow-derived mesenchymal stem cells (MSCs) are able to migrate to tumors, where they promote tumorigenesis and cancer metastasis. However, the molecular phenotype of the recruited MSCs at the tumor microenvironment and the genetic programs underlying their role in cancer progression remains largely unknown. By using a three-dimensional rotary wall vessel coculture system in which human MSCs were grown alone or in close contact with LNCaP, C4-2 or PC3 prostate cancer cell lines, we established in vitro matched pairs of normal and cancer-associated MSC derivatives to study the stromal response of MSCs to prostate cancer. We observed that prostate cancer-associated MSCs acquired a higher potential for adipogenic differentiation and exhibited a stronger ability to promote prostate cancer cell migration and invasion compared with normal MSCs both in vitro and in experimental animal models. The enhanced adipogenesis and the pro-metastatic properties were conferred by the high levels of IL-6 secretion by cancer-associated MSCs and were reversible by functionally inhibiting of IL-6. We also found that IL-6 is a direct target gene for the let-7 microRNA, which was downregulated in cancer-associated MSCs. The overexpression of let-7 via the transfection of let-7 precursors decreased IL-6 expression and repressed the adipogenic potential and metastasis-promoting activity of cancer-associated MSCs, which was consistent with the inhibition of IL-6 3'UTR luciferase activity. Conversely, the treatment of normal MSCs with let-7 inhibitors resulted in effects similar to those seen with IL-6. Taken together, our data demonstrated that MSCs co-evolve with prostate cancer cells in the tumor microenvironment, and the downregulation of let-7 by cancer-associated MSCs upregulates IL-6 expression. This upregulation triggers adipogenesis and facilitates prostate cancer progression. These findings not only provide key insights into the molecular basis of tumor-stroma interactions but also pave the way for new treatments for metastatic prostate cancer.
骨髓间充质干细胞（MSCs）能够迁移到肿瘤部位，在那里促进肿瘤发生和癌症转移。然而，在肿瘤微环境中募集的 MSCs 的分子表型以及它们在癌症进展中作用的遗传程序在很大程度上仍然未知。通过使用三维旋转壁容器共培养系统，将人 MSCs 单独培养或与 LNCaP、C4-2 或 PC3 前列腺癌细胞系紧密接触，我们建立了体外匹配的正常和癌相关 MSC 衍生物对，以研究 MSCs 对前列腺癌的基质反应。我们观察到，与正常 MSCs 相比，前列腺癌相关的 MSCs 获得了更高的脂肪生成分化潜力，并表现出更强的促进前列腺癌细胞迁移和侵袭的能力，无论是在体外还是在实验动物模型中。这种增强的脂肪生成和促转移特性是由癌相关 MSCs 高水平分泌的白细胞介素 6（IL-6）赋予的，并且通过功能抑制 IL-6 是可逆的。我们还发现，IL-6 是 let-7 微 RNA 的直接靶基因，而 let-7 在癌相关 MSCs 中下调。通过转染 let-7 前体，过表达 let-7 可降低 IL-6 表达，抑制癌相关 MSCs 的脂肪生成潜力和促转移活性，与抑制 IL-6 3'UTR 荧光素酶活性一致。相反，用 let-7 抑制剂处理正常 MSCs 会产生与 IL-6 相似的作用。总之，我们的数据表明，MSCs 在肿瘤微环境中与前列腺癌细胞共同进化，癌相关 MSCs 中 let-7 的下调上调了 IL-6 的表达。这种上调触发了脂肪生成，并促进了前列腺癌的进展。这些发现不仅为肿瘤-基质相互作用的分子基础提供了关键见解，也为转移性前列腺癌的新治疗方法铺平了道路。
