A platform of patient-derived tumor xenografts (EOC-xenografts) to recapitulate the clinicopathology and genetic alterations of ovarian cancer. Homo sapiens

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. On the basis of its histopathology and molecular-genomic changes ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC-xenografts that recapitulate the molecular and biological heterogeneity of human ovarian cancer. Thirty-four EOC-xenografts were successfully established, either subcutaneously or intraperitoneally, in nude mice. The xenografts were histologically similar to the corresponding patient tumor and comprised all the major ovarian cancer subtypes. After orthotopic transplantation in the bursa of the mouse ovary, they disseminate into the organs of the peritoneal cavity and produce ascites, typical of ovarian cancer. Gene expression analysis and mutation status indicated a high degree of similarity with the original patient and discriminate different subsets of xenografts. They were very responsive, responsive and resistant to cisplatin, resembling the clinical situation in ovarian cancer. This panel of patient-derived EOC-xenografts that recapitulate the recently type I and type II classification serves to study the biology of ovarian cancer, identify tumor-specific molecular markers and develop novel treatment modalities. Overall design: EOC-xenografts collected from subcutis, abdominal masses and ascitic fluid of mice engrafted with tumors at different passages (from 1 to 6) and from patient specimens, underwent one-color microarray-based gene expression profiling. To assess the amount of human- and mouse-derived cells in the xenograft tumors, total RNA was evaluated by species specific qPCR assays for beta actin. Only samples with a human RNA content > 75% were analyzed. Nine patient specimens and 62 xenograft samples (representing 29 EOC-xenograft models) underwent gene expression analysis with SurePrint G3 Human GE V2 8x60K microarrays.

上皮性卵巢癌（Epithelial Ovarian Cancer, EOC）是致死率最高的妇科恶性肿瘤。根据组织病理学特征与分子基因组改变，卵巢癌可分为多个亚型，各亚型具有独特的生物学特性与临床预后。本研究旨在构建一组可复现人类卵巢癌分子与生物学异质性的患者来源上皮性卵巢癌异种移植瘤（patient-derived EOC-xenografts）模型。研究人员成功在裸鼠体内通过皮下或腹腔内接种的方式建立了34株异种移植瘤模型。该系列异种移植瘤的组织学特征与对应患者肿瘤高度相似，涵盖了所有主要的卵巢癌亚型。将其原位移植至小鼠卵巢囊后，肿瘤可播散至腹膜腔各脏器并产生腹水，这与人类卵巢癌的典型临床表型一致。基因表达分析与突变状态检测结果显示，该模型与原始患者肿瘤具有高度相似性，且可有效区分不同的异种移植瘤亚群。模型对顺铂分别表现出高敏感、敏感与耐药三种响应表型，精准模拟了卵巢癌患者的临床治疗响应情况。本系列可复现I型与II型分类的患者来源上皮性卵巢癌异种移植瘤模型，可用于卵巢癌生物学机制研究、肿瘤特异性分子标志物筛选以及新型治疗手段开发。

整体实验设计：研究人员收集了不同传代（1至6代）接种于小鼠皮下、腹腔肿物及腹水中的异种移植瘤组织，以及患者原发肿瘤标本，对其开展单通道微阵列基因表达谱分析。为评估异种移植瘤中人与小鼠来源细胞的占比，研究人员通过物种特异性定量聚合酶链反应（qPCR）检测β肌动蛋白的表达水平，仅选取人源RNA占比＞75%的样本进行后续分析。最终，9例患者标本与62例异种移植瘤样本（对应29株上皮性卵巢癌异种移植瘤模型）通过SurePrint G3 Human GE V2 8x60K微阵列完成了基因表达分析。