Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer
Characterization of a Large Panel of Patient-Derived Tumor Xenografts Representing the Clinical Heterogeneity of Human Colorectal Cancer
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DOI：
10.1158/1078-0432.ccr-12-0372
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发表时间：
2012-10-01
影响因子：
11.5
通讯作者：
Berthet, Cyril
中科院分区：
文献类型：
--
作者：
Julien, Sylvia;Merino-Trigo, Ana;Berthet, Cyril
目的：患者来源的异种移植模型被认为代表了人类癌症和先进的临床前模型的异质性。我们的联盟共同努力，广泛开发和表征一种新的患者来源的结直肠癌(CRC)模型。实验设计：从收集的85例无监督的外科结直肠标本中，54例肿瘤成功地移植到免疫缺陷小鼠和大鼠身上，代表35例原发肿瘤，5例腹膜癌和14例转移瘤。患者肿瘤的组织学和分子生物学特征，小鼠的第一代和晚期传代包括与结直肠癌相关的关键基因的序列(即APC，KRAS，TP53)，aCGH，和转录分析。结果：这些综合的特征表明，我们的收集概括了关于结直肠癌组织病理学和分子多样性的临床情况。此外，患者肿瘤和相应的模型正在聚集在一起，允许在临床和临床前数据之间进行比较研究。因此，我们对结直肠癌(5-氟尿嘧啶、奥沙利铂、伊立替康和西妥昔单抗)进行了药物单一疗法的标准治疗研究。通过这种广泛的体内分析，我们已经显示了植入后人基质细胞的丢失，在一些模型中观察到了转移表型，最后比较了每种肿瘤模型的分子图谱和药物敏感性。通过实验性的西妥昔单抗II期试验，我们证实了KRAS突变在西妥昔单抗耐药中的关键作用。结论：这一新的收集有助于评估新的靶向治疗策略，并更好地了解个体患者肿瘤的敏感性或耐药性的基础。临床癌症资源；18(19)；5314-28。(C)2012年AACR。
Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis.Results: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance.Conclusions: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients. Clin Cancer Res; 18(19); 5314-28. (C)2012 AACR.