Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma.
Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma.
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患者来源的细胞系和腹膜癌转移原位小鼠模型重现了人胃腺癌的分子和表型特征。
DOI：
10.1186/s13046-021-02003-8
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发表时间：
2021-06-23
期刊：
影响因子：
--
通讯作者：
Ajani JA
中科院分区：
文献类型：
--
作者：
Song S;Xu Y;Huo L;Zhao S;Wang R;Li Y;Scott AW;Pizzi MP;Wang Y;Fan Y;Harada K;Jin J;Ma L;Yao X;Shanbhag ND;Gan Q;Roy-Chowdhuri S;Badgwell BD;Wang Z;Wang L;Ajani JA
伴有腹膜癌转移（PC）的胃腺癌具有治疗抗性，且生存率低。为深入研究PC，迫切需要开发具有代表性的源自PC的细胞系和转移模型，以研究PC的分子机制，并用于新疗法的临床前筛选。
从患者来源的PC细胞中开发了PC细胞系。通过皮下（人源肿瘤异种移植模型，PDXs）和原位接种研究其致瘤性和转移潜能。进行了核型分析、全外显子组测序、RNA测序以及功能研究，以便从分子层面定义这些细胞系，并比较PDX和供体PC细胞的基因组及表型特征。
我们建立了三种PC细胞系（GA0518、GA0804和GA0825），并在体外对其进行了表征。GA0518、GA0804和GA0825的倍增时间分别为22小时、39小时和37小时。癌症干细胞标志物（CD44、ALDH1、CD133和YAP1）的表达以及癌基因的激活在这些细胞系中各不相同。所有三种PC细胞系均形成了PDXs。有趣的是，所有三种PC细胞系在患者来源的原位（PDO）模型中均形成肿瘤，并且GA0518细胞系在小鼠中持续产生PC。此外，PDXs重现了供体PC细胞的转录组和表型特征。最后，这些细胞系适用于化疗和靶向药物在体外和体内的临床前测试。
我们成功建立了三种患者来源的PC细胞系以及一种改良的PDO模型，该模型中与恶性腹水相关的PC发生率较高。因此，这些细胞系和转移性PDO模型是深入探索PC转移机制以及通过对胃腺癌进行研究以进行靶向药物筛选和验证的极佳资源，可用于转化研究。
在线版本包含补充材料，可在10.1186/s13046 - 021 - 02003 - 8获取。
Gastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies. PC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells. We established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo. We successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies. The online version contains supplementary material available at 10.1186/s13046-021-02003-8.
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影响因子：
4.3
作者：
Gao JP;Xu W;Liu WT;Yan M;Zhu ZG
通讯作者：
Zhu ZG
CD44 阳性癌症干细胞样细胞在胃癌侵袭性前沿的预后影响。
影响因子：
8.8
作者：
Kodama H;Murata S;Ishida M;Yamamoto H;Yamaguchi T;Kaida S;Miyake T;Takebayashi K;Kushima R;Tani M
通讯作者：
Tani M
影响因子：
2.9
作者：
Feng HY;Zhang Y;Liu HJ;Dong X;Yang SC;Lu Q;Meng F;Chen HZ;Sun P;Fang C
通讯作者：
Fang C
影响因子：
3.9
作者：
Su X;Xue Y;Wei J;Huo X;Gong Y;Zhang H;Han R;Chen Y;Chen H;Chen J
通讯作者：
Chen J
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.