Dataset Information

Development of a patient-derived xenograft model of glioblastoma via intravitreal injection in mice.

ABSTRACT: Currently, the two primary patient-derived xenograft (PDX) models of glioblastoma are established through intracranial or subcutaneous injection. In this study, a novel PDX model of glioblastoma was developed via intravitreal injection to facilitate tumor formation in a brain-mimicking microenvironment with improved visibility and fast development. Glioblastoma cells were prepared from the primary and recurrent tumor tissues of a 39-year-old female patient. To demonstrate the feasibility of intracranial tumor formation, U-87 MG and patient-derived glioblastoma cells were injected into the brain parenchyma of Balb/c nude mice. Unlike the U-87 MG cells, the patient-derived glioblastoma cells failed to form intracranial tumors until 6 weeks after tumor cell injection. In contrast, the patient-derived cells effectively formed intraocular tumors, progressing from plaques at 2 weeks to masses at 4 weeks after intravitreal injection. The in vivo tumors exhibited the same immunopositivity for human mitochondria, GFAP, vimentin, and nestin as the original tumors in the patient. Furthermore, cells isolated from the in vivo tumors also demonstrated morphology similar to that of their parental cells and immunopositivity for the same markers. Overall, a novel PDX model of glioblastoma was established via the intravitreal injection of tumor cells. This model will be an essential tool to investigate and develop novel therapeutic alternatives for the treatment of glioblastoma.

SUBMITTER: Lee J

PROVIDER: S-EPMC6467997 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Development of a patient-derived xenograft model of glioblastoma via intravitreal injection in mice.

Lee Jooyoung J Jo Dong Hyun DH Kim Jin Hyoung JH Cho Chang Sik CS Han Jiwon Esther JE Kim Yona Y Park Hyoungwoo H Yoo Seung Ho SH Yu Young Suk YS Moon Hyo Eun HE Park Hye Ran HR Kim Dong Gyu DG Kim Jeong Hun JH Paek Sun Ha SH

Experimental & molecular medicine 20190416 4

Currently, the two primary patient-derived xenograft (PDX) models of glioblastoma are established through intracranial or subcutaneous injection. In this study, a novel PDX model of glioblastoma was developed via intravitreal injection to facilitate tumor formation in a brain-mimicking microenvironment with improved visibility and fast development. Glioblastoma cells were prepared from the primary and recurrent tumor tissues of a 39-year-old female patient. To demonstrate the feasibility of intr ...[more]

PMID: 30992429

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Project description:Glioblastoma (GBM) heterogeneity, aggressiveness and infiltrative growth drastically limit success of current standard of care drugs and efficacy of various new therapeutic approaches. There is a need for new therapies and models reflecting the complex biology of these tumors to analyze the molecular mechanisms of tumor formation and resistance, as well as to identify new therapeutic targets. We established and screened a panel of 26 patient-derived subcutaneous (s.c.) xenograft (PDX) GBM models on immunodeficient mice, of which 15 were also established as orthotopic models. Sensitivity toward a drug panel, selected for their different modes of action, was determined. Best treatment responses were observed for standard of care temozolomide, irinotecan and bevacizumab. Matching orthotopic models frequently show reduced sensitivity, as the blood-brain barrier limits crossing of the drugs to the GBM. Molecular characterization of 23 PDX identified all of them as IDH-wt (R132) with frequent mutations in EGFR, TP53, FAT1, and within the PI3K/Akt/mTOR pathway. Their expression profiles resemble proposed molecular GBM subtypes mesenchymal, proneural and classical, with pronounced clustering for gene sets related to angiogenesis and MAPK signaling. Subsequent gene set enrichment analysis identified hallmark gene sets of hypoxia and mTORC1 signaling as enriched in temozolomide resistant PDX. In models sensitive for mTOR inhibitor everolimus, hypoxia-related gene sets reactive oxygen species pathway and angiogenesis were enriched. Our results highlight how our platform of s.c. GBM PDX can reflect the complex, heterogeneous biology of GBM. Combined with transcriptome analyses, it is a valuable tool in identification of molecular signatures correlating with monitored responses. Available matching orthotopic PDX models can be used to assess the impact of the tumor microenvironment and blood-brain barrier on efficacy. Our GBM PDX panel therefore represents a valuable platform for screening regarding molecular markers and pharmacologically active drugs, as well as optimizing delivery of active drugs to the tumor.

Dataset Information

Development of a patient-derived xenograft model of glioblastoma via intravitreal injection in mice.

Publications

Development of a patient-derived xenograft model of glioblastoma via intravitreal injection in mice.

Similar Datasets

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