Jo Eun Byeol, Hong Doopyo, Lee Young Sang, Lee Hyunjoo, Park Jae Berm, Kim Sung Joo
Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul; Transplantation Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea.
Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul.
Transl Oncol. 2019 Feb;12(2):269-281. doi: 10.1016/j.tranon.2018.09.015. Epub 2018 Nov 14.
The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose-dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients.
患者来源的异种移植（PDX）模型已成为研究各种癌症肿瘤发生和分化的主要工具。此外，它还被用于抗癌药物的研发。PDX模型一直是用于了解基质细胞和血管细胞在体内作用的最有意义的工具之一，而基质细胞和血管细胞是癌症发展及治疗药物应用的主要因素。同样，从脂肪肉瘤患者建立PDX模型对于理解脂肪瘤形成及后续药物研发也被认为很重要。出于这些原因，我们建立了来自20例脂肪肉瘤患者的患者来源细胞（PDC）和PDX模型。这些患者的组织是根据三星医疗中心伦理政策的原则获取的，细胞培养和移植到小鼠体内的操作也是在这些原则下进行的。使用已建立的PDC进行高通量药物筛选（HTS）以选择候选药物。在不同的候选抗癌药物中，我们测试了硼替佐米的效果，预期它能抑制MDM2扩增。首先，我们通过荧光原位杂交评估MDM2扩增和CDK4过表达，证实PDC保持了脂肪肉瘤细胞的特征。短串联重复序列分析和使用比较基因组杂交的阵列证实PDX模型表现出与患者相同的基因组图谱。对MDM2和CDK4的免疫组织化学分析表明，这两种蛋白在PDX模型和PDC中的过表达模式相似。具体而言，观察到MDM2扩增与PDX小鼠模型的成功建立显著相关。然而，CDK4表达并未显示出这种相关性。在通过HTS选择的抗癌药物中，硼替佐米对PDC显示出强大的抗癌作用。此外，我们观察到硼替佐米以剂量依赖性方式抑制MDM2表达。相反，p21倾向于使PDC表达增加。用硼替佐米治疗PDX模型产生了与PDC中相似的抗癌效果。这些结果支持PDC和PDX模型是用于脂肪肉瘤患者抗癌药物研发和临床应用的最强大工具之一。
