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Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type.

ABSTRACT: The pathogenesis of canine T-cell lymphoma remains incompletely understood, partly because there are no well-established in-vivo models to study these malignancies. For this study, we generated a patient-derived tumour xenograft (PDTX) from a 10-year-old neutered male golden retriever dog with enteropathy-associated intestinal T-cell lymphoma, large cell type. One of two female, 15-week-old beige/nude/XID mice developed a visible tumour 7 weeks after sections of tumour material from the spleen were surgically implanted. The histological appearance, immunophenotype and clonal antigen receptor rearrangements of the tumour from the recipient mouse showed that it was derived from the primary canine tumour. Our results indicate that immunodeficient mice are receptive hosts to develop in-vivo PDTX models to study the pathogenesis and management of canine T-cell lymphomas.

SUBMITTER: Im KS

PROVIDER: S-EPMC5292073 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type.

Im K S KS Kim J H JH Graef A J AJ Cornax I I Seelig D M DM O'Sullivan M G MG Kovi R C RC Modiano J F JF

Journal of comparative pathology 20161220 1

The pathogenesis of canine T-cell lymphoma remains incompletely understood, partly because there are no well-established in-vivo models to study these malignancies. For this study, we generated a patient-derived tumour xenograft (PDTX) from a 10-year-old neutered male golden retriever dog with enteropathy-associated intestinal T-cell lymphoma, large cell type. One of two female, 15-week-old beige/nude/XID mice developed a visible tumour 7 weeks after sections of tumour material from the spleen w ...[more]

PMID: 28011041

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Project description:Patient-derived xenografts (PDX) have a biologically stable in tumor architecture, drug responsiveness, mutational status and global gene-expression patterns. Numerous PDX models have been established to date, however their thorough characterization regarding the tumor formation and rates of tumor growth in the established models remains a challenging task. Our study aimed to provide more detailed information for establishing the PDX models successfully and effectively.We transplanted four different types of solid tumors from 108 Chinese patients, including 21 glioblastoma (GBM), 11 lung cancers (LC), 54 gastric cancers (GC) and 21 colorectal cancers (CRC), and took tumor tissues passaged for three successive generations. Here we report the rate of tumor formation, tumor-forming times, tumor growth curves and mortality of mice in PDX model. We also report H&E staining and immunohistochemistry for HLA-A, CD45, Ki67, GFAP, and CEA protein expression between patient cancer tissues and PDX models.Tumor formation rate increased significantly in subsequent tumor generations. Also, the survival rates of GC and CRC were remarkably higher than GBM and LC. As for the time required for the formation of tumors, which reflects the tumor growth rate, indicated that tumor growth rate always increased as the generation number increased. The tumor growth curves also illustrate this law. Similarly, the survival rate of PDX mice gradually improved with the increased generation number in GC and CRC. And generally, there was more proliferation (Ki67+) in the PDX models than in the patient tumors, which was in accordance with the results of tumor growth rate. The histological findings confirm similar histological architecture and degrees of differentiation between patient cancer tissues and PDX models with statistical analysis by GraphPad Prism 5.0.We established four different types of PDX models successfully, and our results add to the current understanding of the establishment of PDX models and may contribute to the extension of application of different types of PDX models.

Project description:BackgroundNon-gestational choriocarcinoma (NGC) is a rare subtype of malignant germ cell tumour and there is no consensus on its treatment. The lack of suitable preclinical models for NGC is a challenge in drug discovery research. Patient-derived xenograft (PDX) models recapitulate the tumour microenvironment of the original cancer tissue. Therefore, they have received considerable attention for studies on rare cancer. Here, we aimed to establish a PDX model from a patient with recurrent NGC.MethodsFresh NGC tumour tissue was immediately transplanted into a severely immune-deficient mouse (NOD.Cg-Prkdcscid1l2rgtm1Wjl/SzJ) and maintained for more than three in vivo passages. Subsequently, we evaluated the molecular characteristics of the PDX model using immunohistochemistry, polymerase chain reaction, and RNA sequencing. Moreover, the PDX tumours were transplanted into BALB/c nude mice, and we evaluated their sensitivity for cisplatin and methotrexate.ResultsThe PDX tumour maintained the morphological features of NGC. Moreover, Immunohistochemistry revealed that the human chorionic gonadotropin, cytokeratin 7, and EpCAM expression levels were similar to those in the primary tumour. Furthermore, serum human chorionic gonadotropin levels were elevated in both the primary tumour and the PDX models. Additionally, using PCR analysis with species-specific primers, we confirmed that the PDX tumour contained human genes and was derived from human tissue. Moreover, the gene expression profile of the NGC was compared with that of epithelial ovarian cancer samples and cell lines, and 568 dysregulated genes in the NGC were extracted. The expression of the dysregulated genes in PDX was significantly correlated with that in the primary tumour (R2 = 0.873, P < 0.001). Finally, we demonstrated that the PDX tumour was sensitive to cisplatin and methotrexate; therefore, its clinical response to the agents was similar to that of the primary tumour.ConclusionsWe successfully established a PDX model of NGC, to the best of our knowledge, for the first time. The established PDX retained the molecular and transcriptome characteristics of the primary tumour and can be used to predict drug effects. It may facilitate further research and the development of novel therapeutic agents for NGC.

Dataset Information

Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type.

Publications

Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type.

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