Molecular Characterization of Patient-Derived Human Pancreatic Tumor Xenograft Models for Preclinical and Translational Development of Cancer Therapeutics
Molecular Characterization of Patient-Derived Human Pancreatic Tumor Xenograft Models for Preclinical and Translational Development of Cancer Therapeutics
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DOI：
10.1593/neo.13922
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发表时间：
2013-10-01
期刊：
影响因子：
4.8
通讯作者：
Challita-Eid, Pia
中科院分区：
文献类型：
--
作者：
Mattie, Mike;Christensen, Ashley;Challita-Eid, Pia
新型抗癌药物的临床前评价需要准确反映人类肿瘤生物学和分子特征的模型。将八个胰腺导管腺癌患者肿瘤的分子谱与通过将肿瘤片段移植到免疫受损小鼠中获得的异种移植物的相应传代进行比较。通过拷贝数分析、基因表达和microRNA微阵列、突变分析、短串联重复序列（STR）分析和免疫组织化学进行分子表征。发现异种移植物高度代表其各自的肿瘤，通过STR分析和突变分析观察到高度的遗传稳定性。早期和晚期异种移植物传代的拷贝数变异（CNV）谱相似，染色体1p、3p、4q、6、8p、9、10、11q、12p、15q、17、18、20p和21上的复发性丢失和1q、5p、8q、11q、12q、13q、19q和20q上的增加。对于所有模型，肿瘤和异种移植物传代的基因表达谱的Pearson相关性均在0.88以上。对于每个单独的模型，早期和晚期传代异种移植物之间的基因表达模式高度稳定。在异种移植物传代中观察到的变化在很大程度上对应于人基质区室基因和炎症过程。虽然原发性肿瘤和相应的异种移植物之间存在一些差异，但在广泛传代后分子谱保持稳定。几轮传代后分子特征稳定性的证据为临床相关性提供了信心，并允许扩展模型以生成药物筛选和开发研究中使用的队列所需的必要数量的动物。
Preclinical evaluation of novel cancer agents requires models that accurately reflect the biology and molecular characteristics of human tumors. Molecular profiles of eight pancreatic ductal adenocarcinoma patient tumors were compared to corresponding passages of xenografts obtained by grafting tumor fragments into immuno-compromised mice. Molecular characterization was performed by copy number analysis, gene expression and microRNA microarrays, mutation analysis, short tandem repeat (STR) profiling, and immunohistochemistry. Xenografts were found to be highly representative of their respective tumors, with a high degree of genetic stability observed by STR profiling and mutation analysis. Copy number variation (CNV) profiles of early and late xenograft passages were similar, with recurrent losses on chromosomes 1p, 3p, 4q, 6, 8p, 9, 10, 11q, 12p, 15q, 17, 18, 20p, and 21 and gains on 1q, 5p, 8q, 11q, 12q, 13q, 19q, and 20q. Pearson correlations of gene expression profiles of tumors and xenograft passages were above 0.88 for all models. Gene expression patterns between early and late passage xenografts were highly stable for each individual model. Changes observed in xenograft passages largely corresponded to human stromal compartment genes and inflammatory processes. While some differences exist between the primary tumors and corresponding xenografts, the molecular profiles remain stable after extensive passaging. Evidence for stability in molecular characteristics after several rounds of passaging lends confidence to clinical relevance and allows for expansion of models to generate the requisite number of animals required for cohorts used in drug screening and development studies.