Microsatellite instability-high colorectal cancer patient-derived xenograft models for cancer immunity research
| Autor: | Yoshiaki Nagatani, Hironobu Minami, Yohei Funakoshi, Takeru Matsuda, Shinwa Tanaka, Hiroshi Hasegawa, Yoshihiro Kakeji, Hirotaka Suto, Naomi Kiyota, Yoshinori Imamura, Kimihiro Yamashita, Masanori Toyoda, Hisayuki Matsumoto, Ryo Takai |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Colorectal cancer Apoptosis Cancer immunity Mice SCID DNA Mismatch Repair Mice Mice Inbred NOD Tumor Cells Cultured Animals Humans Medicine Radiology Nuclear Medicine and imaging Tumor xenograft Aged Cell Proliferation Aged 80 and over business.industry Microsatellite instability General Medicine DNA Methylation Middle Aged medicine.disease Xenograft Model Antitumor Assays Oncology Mutation Leukocytes Mononuclear Cancer research Female Microsatellite Instability Immunotherapy Colorectal Neoplasms MutL Protein Homolog 1 business |
| Zdroj: | Journal of Cancer Research and Therapeutics. 17:1358 |
| ISSN: | 0973-1482 |
| DOI: | 10.4103/jcrt.jcrt_1092_20 |
| Popis: | There is an increasing demand for appropriate preclinical mice models for evaluating the efficacy of cancer immunotherapies.Therefore, we established a humanized patient-derived xenograft (PDX) model using microsatellite instability-high (MSI-H) colorectal cancer (CRC) tissues and patient-derived peripheral blood mononuclear cells (PBMCs).The CRC tissues of patients scheduled for surgery were tested for MSI status, and CRC tumors were transplanted into NOD/LtSz-scid/IL-2Rg-/-(NSG) mice to establish MSI-H PDX models. PDX tumors were compared to the original patient tumors in terms of histological and genetic characteristics. To humanize the immune system of MSI-H PDX models, patient PBMCs were injected through the tail vein.PDX models were established from two patients with MSI-H CRC; one patient had a germline mutation in MLH1 (c.1990-2AG), and the other patient had MLH1 promoter hypermethylation. PDX with the germline mutation was histologically similar to the patient tumor, and retained the genetic characteristics, including MSI-H, deficient mismatch repair (dMMR), and MLH1 mutation. In contrast, the histological features of the other PDX from a tumor with MLH1 promoter hypermethylation were clearly different from those of the original tumor, and MLH1 promoter hypermethylation and MSI-H/dMMR were lost in the PDX. When T cells from the same patient with MLH1 mutation were injected into the PDX through the tail vein, they were detected in the PDX tumor.The MSI-H tumor with an MMR mutation is suitable for MSI-H PDX model generation. The PBMC humanized MSI-H PDX has the potential to be used as an efficient model for cancer immunotherapy research. |
| Databáze: | OpenAIRE |
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