当前位置: X-MOL 学术Neoplasia › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment
Neoplasia ( IF 4.8 ) Pub Date : 2019-11-20 , DOI: 10.1016/j.neo.2019.10.005
Yuli Lin , Bingji Li , Xuguang Yang , Qian Cai , Weiren Liu , Mengxin Tian , Haoyang Luo , Wei Yin , Yan Song , Yinghong Shi , Rui He

Desmoplasia is a hallmark of intrahepatic cholangiocarcinoma (ICC), which constitutes a barrier to infiltration of lymphocyte, but not myeloid cells. Given that dense desmoplastic stroma has been reported to be a barrier to infiltration of lymphocyte, but not myeloid cells. We here investigated whether fibroblastic FAP influenced ICC progression via non-T cell-related immune mechanisms. We demonstrated fibroblastic FAP expression was critical for STAT3 activation and CCL2 production, and ICC-CAFs were the primary source of CCL2 in human ICC microenvironment by using ICC-Fbs from six ICC patients. Fibroblastic knockdown of FAP significantly impaired the ability of ICC-CAFs to promote ICC growth, MDSCs infiltration and angiogenesis, which was restored by adding exogenous CCL2. Furthermore, interestingly, the tumor-promoting effect of fibroblastic FAP is dependent on MDSCs via secretion of CCL2, as depletion of Gr-1+ cells reversed the restoring effects of exogenous CCL2 on tumor growth and angiogenesis. In vitro migration assay confirmed that exogenous CCL2 could rescue the impaired ability of ICC-Fbs to attract Gr-1+ cells caused by fibroblastic FAP knockdown. In contrast, fibroblastic FAP knockdown had no effect on ICC cell proliferation and apoptotic resistance. Depletion MDSCs by anti-Gr-1 monoclonal antibody in subcutaneous transplanted tumor model abrogated tumor promotion by ICC-CAFs suggested that the pro-tumor function of Fibroblastic FAP relied on MDSCs. Mechanical, flow cytometry and chamber migration assay were conducted to find Fibroblastic FAP was required by the ability of ICC-CAFs to promote MDSC migration directly. Moreover, fibroblastic FAP knockdown had no effect on cell proliferation and apoptotic resistance. Here, we revealed the T-cell independent mechanisms underlying the ICC-promoting effect of fibroblastic FAP by attracting MDSCs via CCL2, which was mainly attributed to the ability of FAP to attract MDSCs and suggests that specific targeting fibroblastic FAP may represent a promising therapeutic strategy against ICC.



中文翻译:

成纤维细胞FAP通过募集MDSC促进肝内胆管癌的生长

异型增生是肝内胆管癌(ICC)的标志,它构成了对淋巴细胞而非骨髓细胞浸润的屏障。考虑到据报道致密的增生基质是阻碍淋巴细胞浸润的屏障,而不是髓样细胞浸润的屏障。我们在这里调查了成纤维细胞FAP是否通过非T细胞相关的免疫机制影响ICC进展。我们证明了成纤维细胞FAP表达对于STAT3激活和CCL2产生至关重要,并且通过使用来自六名ICC患者的ICC-Fb,ICC-CAFs是人类ICC微环境中CCL2的主要来源。FAP的成纤维细胞抑制作用显着削弱了ICC-CAFs促进ICC生长,MDSCs浸润和血管生成的能力,通过添加外源CCL2可以恢复这种能力。此外,有趣的是,+细胞逆转了外源性CCL2对肿瘤生长和血管生成的恢复作用。体外迁移试验证实,外源CCL2可以挽救ICC-Fbs吸引Gr-1 +的能力受损。FAP敲低引起的成纤维细胞。相反,成纤维细胞FAP敲低对ICC细胞增殖和凋亡抗性没有影响。皮下移植肿瘤模型中抗Gr-1单克隆抗体消耗的MDSC消除了ICC-CAF促进肿瘤的发展,提示成纤维FAP的促肿瘤功能依赖于MDSC。进行了机械,流式细胞术和腔室迁移分析,以发现成纤维细胞FAP是ICC-CAF直接促进MDSC迁移的能力所必需的。此外,成纤维细胞FAP敲低对细胞增殖和凋亡抗性没有影响。在这里,我们揭示了通过经由CCL2吸引MDSC,从而使成纤维细胞FAP的ICC促进作用所依赖的T细胞独立机制,

更新日期:2019-11-20
down
wechat
bug