Critical role of PPARγ in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis.
Critical role of PPARγ in myeloid-derived suppressor cell-stimulated cancer cell proliferation and metastasis.
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DOI：
10.18632/oncotarget.6414
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发表时间：
2016-01-12
期刊：
影响因子：
--
通讯作者：
Yan C
中科院分区：
文献类型：
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作者：
Zhao T;Du H;Blum JS;Yan C
溶酶体酸性脂肪酶(Lal)是髓系抑制细胞(MDSCs)中控制中性脂代谢信号的关键酶。LAL缺陷(LAL−/−)小鼠的MDSCs直接刺激癌细胞增殖。PPARγ配体处理可抑制LAL−/−MDSCs对体内肿瘤细胞生长和转移的刺激，以及体外肿瘤细胞的增殖和迁移。此外，PPARγ配体治疗可抑制LAL−/−MDSCs跨内皮细胞的迁移，以及与谱系阴性细胞的分化。PPARγ配体对LAL−/−MDSCs功能的纠正作用是通过调节哺乳动物靶标雷帕霉素(MTOR)途径，进而阻断MDSCs ROS的过量产生而实现的。此外，在髓系特异性显性阴性PPARγ(dnPPARγ)过表达的双转基因小鼠模型中，肿瘤的生长和转移得到促进，这些小鼠的MDSCs刺激了肿瘤细胞的增殖和迁移。DnPPARγ高表达的MDSCs表现为内皮迁移增加，mTOR通路过度激活，ROS产生过多。这些结果表明，PPARγ在LAL调控的中性脂代谢信号转导中起关键作用，为临床靶向MDSCs降低肿瘤的增殖、生长和转移风险提供了机制基础。
Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal−/−) mice directly stimulate cancer cell proliferation. PPARγ ligand treatment inhibited lal−/− MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPARγ ligand treatment impaired lal−/− MDSCs transendothelial migration, and differentiation from lineage-negative cells. The corrective effects of PPARγ ligand on lal−/− MDSCs functions were mediated by regulating the mammalian target of rapamycin (mTOR) pathway, and subsequently blocking MDSCs ROS overproduction. Furthermore, in the myeloid-specific dominant-negative PPARγ (dnPPARγ) overexpression bitransgenic mouse model, tumor growth and metastasis were enhanced, and MDSCs from these mice stimulated tumor cell proliferation and migration. MDSCs with dnPPARγ overexpression showed increased transendothelial migration, overactivation of the mTOR pathway, and ROS overproduction. These results indicate that PPARγ plays a critical role in neutral lipid metabolic signaling controlled by LAL, which provides a mechanistic basis for clinically targeting MDSCs to reduce the risk of cancer proliferation, growth and metastasis.