Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.
Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.
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TEM 和内皮细胞之间的串扰通过 IGF1-IGF1R 信号在上皮性卵巢癌中调节血管生成和转移
DOI：
10.1038/bjc.2017.297
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发表时间：
2017-10-24
影响因子：
8.8
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wang X;Zhu Q;Lin Y;Wu L;Wu X;Wang K;He Q;Xu C;Wan X;Wang X
上皮性卵巢癌(EOC)是妇科恶性肿瘤的主要死亡原因，因转移而预后不良。针对血管生成途径的药物显著改善了患者的预后。然而，与血管生成和转移相关的关键因素尚未阐明。在本研究中，我们发现表达Tie2的单核细胞(CD14+Tie2+，TEMs)在卵巢癌的血管生成和转移中起关键作用。组织切片用免疫荧光法检测总组织巨噬细胞和TEM的存在。计算卵巢癌组织和腹膜组织中微血管密度(MVD)值与TEM数目或比值的相关性。用流式细胞仪检测女性健康献血员、良性囊肿组和卵巢癌患者外周血中单核细胞中TEM的比例。用流式细胞仪检测EOC患者腹水中TEMs的比例。用双抗体夹心ELISA法检测卵巢癌患者血清、良性囊肿患者血清及卵巢癌患者腹水标本中作为Tie2配体的Ang2的浓度。进一步观察Ang2对TEM迁移和细胞因子表达的影响。在体内和体外实验中，通过IGF1对TEM的促血管生成活性进行了研究。用中和抗体进行IGF1阻断试验。卵巢癌患者的肿瘤灶、外周血和腹水中的TEM显著高于对照组。TEM在组织巨噬细胞中所占比例与肿瘤MVD呈正相关。体内动物实验结果表明，TEM可促进EoC血管生成和转移。进一步的功能和机制研究表明，Tie2的配体血管生成素2(Ang2)在EoC腹水中的浓度升高，进一步以剂量依赖的方式招募TEM成为TEM的强大趋化因子。招募的TEM通过IGF1激活的下游信号促进内皮细胞功能。用抑制性抗体封闭分泌的IGF1可减少TEMS介导的血管生成和转移。TEM在EOC患者中显著增加，并通过增加的Ang2被招募到肿瘤部位。TEM升高对卵巢癌具有诊断价值，并与卵巢癌组织中的MVD呈正相关。此外，在体内和体外实验系统中，经Ang2刺激后，TEM均通过IGF1促进血管生成。总之，本研究为开发以Ang2-TEMS-IGF1为轴的新的治疗靶点在EOC中铺平了道路。
Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.
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影响因子：
20.3
作者：
Venneri, Mary Anna;De Palma, Michele;Naldini, Luigi
通讯作者：
Naldini, Luigi
影响因子：
11.2
作者：
Daly, Christopher;Eichten, Alexandra;Thurston, Gavin
通讯作者：
Thurston, Gavin
影响因子：
11.2
作者：
Gopinathan G;Milagre C;Pearce OM;Reynolds LE;Hodivala-Dilke K;Leinster DA;Zhong H;Hollingsworth RE;Thompson R;Whiteford JR;Balkwill F
通讯作者：
Balkwill F
影响因子：
5.3
作者：
PARTANEN, J;ARMSTRONG, E;ALITALO, K
通讯作者：
ALITALO, K
独特的 RNA 转录组模式可能与表达 Tie2 的单核细胞中的血管生成相关
影响因子：
3.5
作者：
Wang, Xinjing;Dai, Zhiyuan;Wang, Xipeng
通讯作者：
Wang, Xipeng