Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis
| Autor: | Mizue Terai, Paolo Fortina, Shinji Ozaki, Ken Kageyama, Andrew E. Aplin, Takami Sato, Kengo Saito, Masahiro Ohara, Michael J. Mastrangelo |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Uveal Neoplasms Genetics and Molecular Biology (all) 0301 basic medicine Pathology Surgical orthotopic implantation Mouse lcsh:Medicine Biochemistry Cryopreservation Mice 0302 clinical medicine Uveal melanoma Tumor Microenvironment Cluster Analysis Melanoma Tumor xenograft Tumor Liver Neoplasms General Medicine Middle Aged Hepatic metastasis 3. Good health Predictive factor Liver 030220 oncology & carcinogenesis Fatal disease Female Adult medicine.medical_specialty Liver tumor DNA Copy Number Variations General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Patient-derived tumor xenograft Cell Line Tumor medicine Animals Humans Aged Mutation Xenograft Model Antitumor Assays Biochemistry Genetics and Molecular Biology (all) business.industry lcsh:R Methodology medicine.disease 030104 developmental biology Cell culture business |
| Zdroj: | Journal of Translational Medicine, Vol 15, Iss 1, Pp 1-19 (2017) Journal of Translational Medicine |
| ISSN: | 1479-5876 |
| Popis: | Background Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice. Results By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice. Conclusions Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1247-z) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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