Development and Characterization of Clinically Relevant Tumor Models From Patients With Renal Cell Carcinoma
Development and Characterization of Clinically Relevant Tumor Models From Patients With Renal Cell Carcinoma
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DOI：
10.1016/j.eururo.2010.11.043
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发表时间：
2011-04-01
期刊：
影响因子：
23.4
通讯作者：
Wood, Christopher G.
中科院分区：
文献类型：
--
作者：
Karam, Jose A.;Zhang, Xiu-Ying;Wood, Christopher G.
背景：动物模型有助于了解疾病的病理生理、治疗作用的机制和体内耐药。目的：建立和鉴定一组根治性肾切除患者来源的小鼠肾细胞癌(RCC)模型。设计、制作和对象：体内和体外动物实验。方法：将手术中获得的肿瘤组织植入雌性BALB/c裸鼠的皮下，并连续传代到新生的小鼠。肿瘤组织学、短串联重复序列(STR)指纹图谱、von Hippel-Lindau(VHL)基因测序和单核苷酸多态性(SNP)分析。荷瘤小鼠接受舒尼替尼或伊波利莫斯治疗。原代细胞培养取自患者肿瘤，并用携带荧光素酶基因的慢病毒进行转基因。建立了乳头状肾癌、乳头状肾细胞癌、透明细胞肾癌和透明细胞肾癌4种皮下移植模型。结果与局限性：从4例不同组织学类型的肾细胞癌患者身上建立了肾细胞癌模型。肿瘤的生长取决于组织学类型、植入的肿瘤芯片的大小和传代次数。小鼠肿瘤准确地代表了它们各自的原始患者肿瘤，因为STR指纹匹配，组织学可比，SNP图谱和VHL突变状态以多代保存。生物发光成像结果与异种皮下移植的生长模式相符。用舒尼替尼和伊维莫司治疗的小鼠表现出初步的反应，随后出现对这些药物的后期耐药，这与临床观察到的RCC患者的情况类似。结论：我们建立了4种具有透明细胞和乳头状组织学特征的RCC异种移植模型，具有稳定的组织学和分子特征。这些模型可以用来了解肾癌的基本生物学以及对治疗的反应和抵抗。(C)2010年欧洲泌尿外科协会。爱思唯尔出版，版权所有。
Background: Animal models are instrumental in understanding disease pathophysiology and mechanisms of therapy action and resistance in vivo.Objective: To establish and characterize a panel of mouse models of renal cell carcinoma (RCC) derived from patients undergoing radical nephrectomy.Design, setting, and participants: In vivo and in vitro animal experiments.Measurements: Tumor tissues obtained during surgery were implanted into the subcutaneous space of female BALB/c nude mice and serially passaged into new mice. Tumors were characterized by histology, short tandem repeat (STR) fingerprinting, von Hippel-Lindau (VHL) gene sequencing, and single nucleotide polymorphism (SNP) analysis. Tumor-bearing mice were treated with sunitinib or everolimus. Primary cell cultures were derived from patient tumors and transfected with a lentivirus carrying the luciferase gene. Four subcutaneous xenograft mouse models were developed, representing papillary type 1, papillary type 2, clear cell, and clear cell with sarcomatoid features RCC.Results and limitations: RCC mouse models were established from four patients with distinct histologies of RCC. Tumor growth was dependent on histologic type, the size of the implanted tumor chip, and the passage number. Mouse tumors accurately represented their respective original patient tumors, as STR fingerprints were matching, histology was comparable, and SNP profiles and VHL mutation status were conserved with multiple passages. Bioluminescence imaging results were commensurate with subcutaneous xenograft growth patterns. Mice treated with sunitinib and everolimus exhibited an initial response, followed by a later stage of resistance to these agents, which mimics the clinical observations in patients with RCC.Conclusions: We developed four mouse xenograft models of RCC with clear-cell and papillary histologies, with stable histologic and molecular characteristics. These models can be used to understand the basic biology of RCC as well as response and resistance to therapy. (C) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.