Spatiotemporal regulation of cholangiocarcinoma growth and dissemination by peritumoral myofibroblasts in a Vcam1-dependent manner.
Spatiotemporal regulation of cholangiocarcinoma growth and dissemination by peritumoral myofibroblasts in a Vcam1-dependent manner.
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DOI：
10.1038/s41388-023-02639-0
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发表时间：
2023-04
期刊：
影响因子：
8
通讯作者：
Zhu L
中科院分区：
文献类型：
--
作者：
Tian C;Li L;Pan Q;Xu B;Li Y;Fan L;Brown A;Morrison M;Dey K;Yang JJ;Yu J;Glazer ES;Zhu L
肝内胆管细胞癌（iCCA）的特点是其高度促纤维增生的基质。肌成纤维细胞（MF）存在于肿瘤块（肿瘤内MF，iMF）和肿瘤边界（肿瘤周围MF，pMF）。使用基于球体的共培养系统，我们表明初始的iCCA-pMF接触对肿瘤细胞具有生长抑制作用。然而，延长的iCCA-pMF相互作用导致显著的肿瘤细胞侵袭和扩散。我们发现，血管细胞粘附分子-1（Vcam 1）水平升高，在肿瘤细胞接触pMF，但低的播散性肿瘤细胞在体外和体内。对小鼠和患者iCCA肿瘤和Vcam 1敲除（Vcam 1 KO）的基因调控网络分析表明，Vcam 1严重参与上皮向间充质转化。虽然Vcam 1 KO在其单一培养物中对肿瘤细胞生长的影响有限，但Vcam 1 KO球状体在与pMF共培养时表现出即时播散和严重的生长缺陷。当移植到肝脏中时，Vcam 1 KO iCCA细胞显示出类似的播散增加，但在建立原发性和转移性肿瘤方面存在显著缺陷。体内Vcam 1的不完全阻断减小了转移病灶的大小，但增加了转移病灶的数量。总的来说，我们的研究表明，时空调控iCCA的生长和传播的pMF在Vcam 1依赖的方式。
Intrahepatic cholangiocarcinoma (iCCA) is characterized by its highly desmoplastic stroma. Myofibroblasts (MFs) are present both within the tumor mass (intratumoral MFs, iMFs) and at the tumor border (peritumoral MFs, pMFs). Using a spheroid-based coculture system, we show that the initial iCCA-pMF contact is growth suppressive to the tumor cells. However, prolonged iCCA-pMF interaction elicits significant tumor cell invasion and dissemination. We find that vascular cell adhesion molecule-1 (Vcam1) level is elevated in tumor cells in contact with pMFs but low in disseminated tumor cells both in vitro and in vivo. A gene regulatory network analysis of mouse and patient iCCA tumors and Vcam1 knockout (Vcam1KO) demonstrate a heavy involvement of Vcam1 in epithelial-to-mesenchymal transition. While Vcam1KO has only a limited impact on tumor cell growth in their monoculture, Vcam1KO spheroids exhibit instant dissemination and a severe growth defect when cocultured with pMFs. When transplanted into the liver, Vcam1KO iCCA cells show a similar increase in dissemination but a significant defect in establishing primary and metastatic tumors. Incomplete blocking of Vcam1 in vivo reduces the size but increase the number of metastatic lesions. Overall, our study shows a spatiotemporal regulation of iCCA growth and dissemination by pMFs in a Vcam1-dependent manner.
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影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
DOI：
10.1002/hep.27822
发表时间：
2015-08
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ji J;Eggert T;Budhu A;Forgues M;Takai A;Dang H;Ye Q;Lee JS;Kim JH;Greten TF;Wang XW
通讯作者：
Wang XW
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
50.3
作者：
Wieland, Elfriede;Rodriguez-Vita, Juan;Fischer, Andreas
通讯作者：
Fischer, Andreas
影响因子：
24.5
作者：
Xu, L;Hui, AY;Eng, FJ
通讯作者：
Eng, FJ