Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy
Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy
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DOI：
10.1016/j.ygyno.2008.03.011
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发表时间：
2008-08-01
影响因子：
4.7
通讯作者：
Wang, Y. Z.
中科院分区：
文献类型：
--
作者：
Press, Joshua Z.;Kenyon, Jennifer A.;Wang, Y. Z.
目标。人类肿瘤组织异种移植模型可能比细胞系更准确地反映肿瘤生物学。本研究评估了作为连续移植异种移植物生长的原发性人类妇科肿瘤的遗传和表型稳定性。在一种可移植的异种移植物系中，对常规化疗和新型分子靶向化疗的反应进行了评估。将新鲜肿瘤移植至NOD/SCID小鼠肾包膜下。从5个肿瘤（4个卵巢癌和1个子宫肉瘤）中获得可移植肿瘤系，连续移植2-6代。通过CGH阵列、免疫组织化学和BRCA突变分析比较原发肿瘤和相应的可移植异种移植物。分析了已知BRCA1种系突变携带者制备的可移植异种移植物对卡铂/紫杉醇联合治疗和PARP抑制剂（PJ34）的组织病理学反应（肿瘤体积、凋亡和有丝分裂指数）。应用于287特征CGH阵列的无监督分层聚类分析显示，4/5的病例中肿瘤内遗传变异程度较低，第5例（来自网膜样本的透明细胞卵巢癌）的变异程度较大。在所有卵巢癌病例中，用mb -1染色评估原发肿瘤和可移植异种移植物的增殖是一致的。BRCA突变分析确定了种系BRCA1突变，用于进一步检测，该异种移植物对卡铂/紫杉醇化疗有显著反应，包括肿瘤体积和增殖减少，但对聚（adp -核糖）聚合酶-1抑制剂pj34没有反应。来自妇科肿瘤的异种移植物可以在NOD/SCID小鼠肾包膜下连续移植和生长，遗传变化很小。该模型可用于研究肿瘤的进展，确定治疗靶点，并测试肿瘤的治疗方式，这些肿瘤在卵巢癌发生中具有重要意义的基因异常，如BRCA1的缺失。(c) 2008爱思唯尔公司版权所有。
Objectives. Human cancer tissue xenograft models may provide a more accurate reflection of tumor biology than cell lines. This study evaluates the genetic and phenotypic stability of primary human gynecological tumors grown as serially transplanted xenografts. The response to conventional chemotherapy and novel molecular targeted chemotherapy is assessed in one of the transplantable xenograft lines.Methods. Fresh tumor was transplanted beneath the renal capsule of NOD/SCID mice. Transplantable tumor lines were derived from 5 tumors (4 ovarian carcinomas and 1 uterine sarcoma), and serially transplanted for 2-6 generations. Comparisons were made between primary tumor and corresponding transplantable xenografts by CGH array, immunohistochemistry, and BRCA mutation analysis. Transplantable xenografts created from known BRCA1 germline mutation carriers were analyzed for histopathologic response (tumor volume, apoptotic and mitotic indices) to combination carboplatin/paclitaxel and to PARP inhibitor (PJ34).Results. Unsupervised hierarchical cluster analysis applied to a 287 feature CGH array demonstrated a low degree of intratumoral genetic variation in 4/5 cases, with greater degree of variation in the fifth case (clear cell ovarian carcinoma derived from an omental sample). Assessment of proliferation using MIB-1 staining was concordant between primary tumor and transplantable xenograft in all ovarian cancer cases. BRCA mutation analysis identified germline BRCA1 mutation for further testing and this xenograft showed a significant response to carboplatin/paclitaxel chemotherapy, including a decrease in tumor volume and proliferation but did not demonstrate a response to the poly (ADP-ribose) polymerase-1 inhibitor PJ34.Conclusions. Xenografts derived from gynecologic tumors can be serially transplanted and grown under renal capsule of NOD/SCID mice with minimal genetic change. This model may be used to study progression of tumors, identify therapeutic targets, and test treatment modalities in tumors with well-characterized abnormalities in genes of fundamental importance in ovarian carcinogenesis, such as loss of BRCA1. (c) 2008 Elsevier Inc. All rights reserved.