Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer.
Cell line and patient-derived xenograft models reveal elevated CDCP1 as a target in high-grade serous ovarian cancer.
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DOI：
10.1038/bjc.2015.471
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发表时间：
2016-02-16
影响因子：
8.8
通讯作者：
Hooper JD
中科院分区：
文献类型：
--
作者：
Harrington BS;He Y;Davies CM;Wallace SJ;Adams MN;Beaven EA;Roche DK;Kennedy C;Chetty NP;Crandon AJ;Flatley C;Oliveira NB;Shannon CM;deFazio A;Tinker AV;Gilks CB;Gabrielli B;Brennan DJ;Coward JI;Armes JE;Perrin LC;Hooper JD
高级别浆液性卵巢癌（HGSC）的靶向疗法的开发仍然具有挑战性，因为贡献分子途径的定义不明确或表达不均匀。CUB结构域蛋白1（CDCP1）是一种在肺癌、结直肠癌、胰腺癌、肾癌和透明细胞卵巢癌中升高的细胞表面蛋白。免疫组化法检测HGSC和输卵管中CUB结构域蛋白1的表达。检测了靶向CDCP1对体外细胞生长和迁移以及小鼠腹膜内异种移植物生长的影响。开发了三种患者来源的异种移植物（PDX）小鼠模型，并表征了CDCP1表达。检查了单克隆抗CDCP 1抗体对PDX生长的影响。通过蛋白质印迹分析评估Src活化。在77%的HGSC病例中观察到CDCP1升高。CDCP1的沉默降低了体外迁移和非粘附细胞生长以及体内肿瘤负荷。在PDX模型中维持患者样品中CDCP1的表达。CDCP1的抗体阻断显著降低HGSC PDX的生长。在培养的细胞和小鼠异种移植物中观察到CDCP1介导的Src活化。含有CUB结构域的蛋白1在大多数HGSC中过表达。体外和小鼠模型数据表明CDCP 1在HGSC中发挥作用，并且可以靶向抑制这种癌症的进展。
Development of targeted therapies for high-grade serous ovarian cancer (HGSC) remains challenging, as contributing molecular pathways are poorly defined or expressed heterogeneously. CUB-domain containing protein 1 (CDCP1) is a cell-surface protein elevated in lung, colorectal, pancreas, renal and clear cell ovarian cancer. CUB-domain containing protein 1 was examined by immunohistochemistry in HGSC and fallopian tube. The impact of targeting CDCP1 on cell growth and migration in vitro, and intraperitoneal xenograft growth in mice was examined. Three patient-derived xenograft (PDX) mouse models were developed and characterised for CDCP1 expression. The effect of a monoclonal anti-CDCP1 antibody on PDX growth was examined. Src activation was assessed by western blot analysis. Elevated CDCP1 was observed in 77% of HGSC cases. Silencing of CDCP1 reduced migration and non-adherent cell growth in vitro and tumour burden in vivo. Expression of CDCP1 in patient samples was maintained in PDX models. Antibody blockade of CDCP1 significantly reduced growth of an HGSC PDX. The CDCP1-mediated activation of Src was observed in cultured cells and mouse xenografts. CUB-domain containing protein 1 is over-expressed by the majority of HGSCs. In vitro and mouse model data indicate that CDCP1 has a role in HGSC and that it can be targeted to inhibit progression of this cancer.