Laboratory for Translational Medicine, Van Andel Research Institute, Grand Rapids, MI, USA.
J Transl Med. 2012 Jun 18;10:125. doi: 10.1186/1479-5876-10-125.
There is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status.
Fresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection.
Fresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity.
The preservation of the patient's tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.
药物和生物标志物开发领域再次兴起，人们开始使用原发肿瘤移植模型作为新型治疗策略中预测患者肿瘤反应的更好指标。尽管与细胞系衍生的异种移植模型相比具有优势，但将肿瘤移植模型的基因型和表型与供体患者肿瘤进行比较的数据有限，限制了对肿瘤移植模型分子相关性的确定。本报告直接比较了患者肿瘤和衍生的肿瘤移植模型的基因组特征，包括基因表达和致癌突变状态。
将 182 名癌症患者的新鲜肿瘤组织植入免疫缺陷小鼠中，以开发原发患者肿瘤移植模型。对患者肿瘤和由此产生的肿瘤移植模型均进行组织学评估。使用 OncoCarta（Sequenom，圣地亚哥，CA）和人类基因微阵列（Affymetrix，圣克拉拉，CA）平台，分别比较关键致癌基因的体细胞突变和由此产生的肿瘤移植模型的基因表达水平。在代表模型的亚组中，评估了在多个体内世代中建立的肿瘤移植模型的基因组稳定性。将形成肿瘤移植模型的患者肿瘤的基因组与未形成肿瘤移植模型的患者肿瘤的基因组进行比较，以确定成功植入或排斥的可能分子基础。
将 182 名癌症患者的新鲜肿瘤组织植入免疫缺陷小鼠中，成功建立了 49 个肿瘤移植模型，这些模型在组织学和基因组上与原始患者肿瘤具有很强的相似性。在四个肿瘤移植模型世代中，肿瘤移植模型与匹配的患者肿瘤之间的转录组和致癌突变比较稳定。不仅各种肿瘤保留了分化模式，而且支持性基质成分也得以保留。那些在肿瘤移植模型中特异性下调的基因在涉及宿主免疫反应的生物学途径中富集，与宿主的免疫缺陷状态一致。成功形成肿瘤移植模型的患者肿瘤富含细胞信号转导、细胞周期和细胞骨架途径，并表现出免疫原性降低的证据。
保留患者肿瘤的基因组特征和肿瘤微环境支持这样一种观点，即原发患者肿瘤移植模型提供了一个相关的模型，以支持肿瘤学中新治疗策略和个性化医疗方法的转化。
