Activation of mTOR pathway in myeloid-derived suppressor cells stimulates cancer cell proliferation and metastasis in lal(-/-) mice.
Activation of mTOR pathway in myeloid-derived suppressor cells stimulates cancer cell proliferation and metastasis in lal(-/-) mice.
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炎症对癌症转移至关重要，其中骨髓源性抑制细胞（MDSC）是重要的参与者。尽管已知 MDSC 可以抑制免疫监视，但其在直接刺激癌细胞增殖和转移中的作用目前仍不清楚。溶酶体酸性脂肪酶 (LAL) 缺乏会导致 MDSC 在多个器官中的全身扩张和浸润，以及随后的炎症。在 LAL 缺陷 (lal−/−) 小鼠模型中，黑色素瘤在同种异体 lal−/− 小鼠中大量转移，而在异体 lal+/+ 小鼠中由于免疫排斥而受到抑制。在这里，我们首次报道来自 lal−/− 小鼠的 MDSC 直接刺激 B16 黑色素瘤细胞的体外增殖、体内生长和转移。 B16 黑色素瘤细胞体外增殖需要细胞因子，即来自 MDSC 的 IL-1β 和 TNFα。人类 LAL (hLAL) 在 lal−/− 小鼠中的骨髓特异性表达在体外和体内挽救了这些恶性表型。 lal-/- MDSC的促肿瘤功能至少部分是通过哺乳动物雷帕霉素靶点（mTOR）途径的过度激活来介导的。 lal−/− MDSC 中 mTOR、Raptor 或 Rictor 的敲低抑制了它们对癌细胞增殖的刺激，包括 B16 黑色素瘤、LLC 和 Tramp-C2 癌细胞。我们的研究结果表明，LAL在调节MDSCs直接刺激癌细胞增殖的能力中发挥着关键作用，并通过调节mTOR通路克服同种异体小鼠癌症转移的免疫排斥，这为靶向MDSCs降低癌症转移风险提供了机制基础。因此，MDSC具有促进癌症转移的双重功能：抑制免疫监视，刺激癌细胞增殖和生长。
Inflammation critically contributes to cancer metastasis, in which myeloid-derived suppressor cells (MDSCs) are an important participant. Although MDSCs are known to suppress immune surveillance, their roles in directly stimulating cancer cell proliferation and metastasis currently remain unclear. Lysosomal acid lipase (LAL) deficiency causes systemic expansion and infiltration of MDSCs in multiple organs and subsequent inflammation. In the LAL-deficient (lal−/−) mouse model, melanoma metastasized massively in allogeneic lal−/− mice, which was suppressed in allogeneic lal+/+ mice due to immune rejection. Here we report for the first time that MDSCs from lal−/− mice directly stimulated B16 melanoma cell in vitro proliferation, and in vivo growth and metastasis. Cytokines i.e., IL-1β and TNFα from MDSCs are required for B16 melanoma cell proliferation in vitro. Myeloid-specific expression of human LAL (hLAL) in lal−/− mice rescues these malignant phenotypes in vitro and in vivo. The tumor-promoting function of lal−/− MDSCs is mediated, at least in part, through over-activation of the mammalian target of rapamycin (mTOR) pathway. Knockdown of mTOR, Raptor or Rictor in lal−/− MDSCs suppressed their stimulation on proliferation of cancer cells, including B16 melanoma, LLC and Tramp-C2 cancer cells. Our results indicate that LAL plays a critical role in regulating MDSCs ability to directly stimulate cancer cell proliferation, and overcome immune rejection of cancer metastasis in allogeneic mice through modulation of the mTOR pathway, which provides a mechanistic basis for targeting MDSCs to reduce the risk of cancer metastasis. Therefore, MDSCs possess dual functions to facilitate cancer metastasis: suppress immune surveillance, and stimulate cancer cell proliferation and growth.
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影响因子：
6
作者：
Qu, Peng;Shelley, William C.;Yan, Cong
通讯作者：
Yan, Cong
影响因子：
20.3
作者：
Qu, Peng;Yan, Cong;Du, Hong
通讯作者：
Du, Hong
影响因子：
6
作者：
Yan, Cong;Lian, Xuemei;Du, Hong
通讯作者：
Du, Hong
DOI：
10.1038/nrc3581
发表时间：
2013-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.3
作者：
Qu, Peng;Roberts, Jennifer;Li, Yuan;Albrecht, Marjorie;Cummings, Oscar W.;John, N. Eble;Du, Hong;Yan, Cong
通讯作者：
Yan, Cong