Lysosomal acid lipase in mesenchymal stem cell stimulation of tumor growth and metastasis.
Lysosomal acid lipase in mesenchymal stem cell stimulation of tumor growth and metastasis.
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DOI：
10.18632/oncotarget.11244
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发表时间：
2016-09-20
期刊：
影响因子：
--
通讯作者：
Du H
中科院分区：
文献类型：
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作者：
Zhao T;Yan C;Du H
骨髓间充质干细胞（MSC）是肿瘤微环境的重要参与者，促进肿瘤的生长和进展。在此，我们首次报道，在同种异体和同基因小鼠模型中，间充质干细胞中溶酶体酸性脂肪酶（LAL）的消耗会损害其刺激肿瘤生长和转移的能力。在 LAL 缺陷 (lal−/−) MSC 中观察到细胞活力降低，这是细胞周期停滞导致细胞凋亡增加和增殖减少的结果。已知介导 MSC 的肿瘤刺激和免疫抑制作用的细胞因子和趋化因子（即 IL-6、MCP-1 和 IL-10）的合成和分泌在 lal−/− MSC 中下调。当用来自 lal−/− MSC 的条件培养基处理肿瘤细胞时，观察到增殖减少，同时肿瘤细胞中致癌细胞内信号分子的激活减少。将 lal−/− MSC 和 B16 黑色素瘤细胞共同注射到野生型小鼠中，不仅诱导 CD8+ 细胞毒性 T 细胞，而且还减少了促肿瘤 Ly6G+CD11b+ 骨髓源性抑制细胞 (MDSC) 的积累，这可能协同损害肿瘤进展。此外，lal−/− MSCs 向肿瘤相关成纤维细胞的分化能力受损。此外，MDSC 促进 MSC 增殖，这是由 MDSC 分泌的细胞因子和趋化因子介导的。我们的研究结果表明，LAL 在调节 MSC 刺激肿瘤生长和转移的能力中发挥着关键作用，这为靶向 MSC 中的 LAL 降低癌症转移风险提供了机制基础。
Bone marrow mesenchymal stem cells (MSCs) are an important participant in the tumor microenvironment, in which they promote tumor growth and progression. Here we report for the first time that depletion of lysosomal acid lipase (LAL) in MSCs impairs their abilities to stimulate tumor growth and metastasis both in allogeneic and syngeneic mouse models. Reduced cell viability was observed in LAL-deficient (lal−/−) MSCs, which was a result of both increased apoptosis and decreased proliferation due to cell cycle arrest. The synthesis and secretion of cytokines and chemokines that are known to mediate MSCs' tumor-stimulating and immunosuppressive effects, i.e., IL-6, MCP-1 and IL-10, were down-regulated in lal−/− MSCs. When tumor cells were treated with the conditioned medium from lal−/− MSCs, decreased proliferation was observed, accompanied by reduced activation of oncogenic intracellular signaling molecules in tumor cells. Co-injection of lal−/− MSCs and B16 melanoma cells into wild type mice not only induced CD8+ cytotoxic T cells, but also decreased accumulation of tumor-promoting Ly6G+CD11b+ myeloid-derived suppressor cells (MDSCs), which may synergistically contribute to the impairment of tumor progression. Furthermore, lal−/− MSCs showed impaired differentiation towards tumor-associated fibroblasts. In addition, MDSCs facilitated MSC proliferation, which was mediated by MDSC-secreted cytokines and chemokines. Our results indicate that LAL plays a critical role in regulating MSCs' ability to stimulate tumor growth and metastasis, which provides a mechanistic basis for targeting LAL in MSCs to reduce the risk of cancer metastasis.