Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis.
Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis.
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DOI：
10.18632/oncotarget.9486
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发表时间：
2017-04-25
期刊：
影响因子：
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通讯作者：
Yang L
中科院分区：
文献类型：
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作者：
Jian J;Pang Y;Yan HH;Min Y;Achyut BR;Hollander MC;Lin PC;Liang X;Yang L
骨髓来源的髓样细胞可以形成转移前小生境并提供促肿瘤微环境。然而，骨髓细胞的亚群也被报道具有抗肿瘤特性。目前尚不清楚这些髓样细胞的抗肿瘤和促肿瘤功能之间是否存在过渡，如果存在，其潜在的分子机制是什么。在这里，我们报告血小板因子4（PF 4），或CXCL 4，但不是其他家族成员CXCL 9，10和11，在正常肺和早期转移前肺中以较高水平产生，但在晚期肺中降低。PF 4主要由Ly 6 G + CD 11b+髓系细胞亚群产生。虽然Ly 6 G + CD 11b+细胞的数量在转移前肺中增加，但在转移进展过程中这些细胞中PF 4的表达水平降低。PF 4的缺失（PF 4敲除或KO小鼠）导致转移增加，表明PF 4的抑制功能。有两个潜在的机制：在转移前肺血管完整性下降，造血干/祖细胞（HSC）和髓源性抑制细胞（MDSC）的生产增加，在荷瘤PF 4基因敲除小鼠。在癌症患者中，PF 4表达水平与肿瘤分期呈负相关，与患者生存率呈正相关。我们的研究表明，PF 4是一个关键的抗肿瘤因子在转移前的网站。我们发现PF 4在肿瘤宿主中的功能为理解肿瘤转移的机制提供了新的见解。
Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor–promoting microenvironment. However, subsets of myeloid cells have also been reported to have anti-tumor properties. It is not clear whether there is a transition between anti- and pro- tumor function of these myeloid cells, and if so, what are the underlying molecular mechanisms. Here we report platelet factor 4 (PF4), or CXCL4, but not the other family members CXCL9, 10, and 11, was produced at higher levels in the normal lung and early stage premetastatic lungs but decreased in later stage lungs. PF4 was mostly produced by Ly6G+CD11b+ myeloid cell subset. Although the number of Ly6G+CD11b+ cells was increased in the premetastatic lungs, the expression level of PF4 in these cells was decreased during the metastatic progression. Deletion of PF4 (PF4 knockout or KO mice) led an increased metastasis suggesting an inhibitory function of PF4. There were two underlying mechanisms: decreased blood vessel integrity in the premetastatic lungs and increased production of hematopoietic stem/progenitor cells (HSCs) and myeloid derived suppressor cells (MDSCs) in tumor-bearing PF4 KO mice. In cancer patients, PF4 expression levels were negatively correlated with tumor stage and positively correlated with patient survival. Our studies suggest that PF4 is a critical anti-tumor factor in the premetastatic site. Our finding of PF4 function in the tumor host provides new insight to the mechanistic understanding of tumor metastasis.