Orthotopic models of pediatric brain tumors in zebrafish
| Autor: | Yiai Tong, David Finkelstein, Bensheng Ju, Jason Dapper, Richard J. Gilbertson, Nidal Boulos, Michael R. Taylor, Radhika Thiruvenkatam, Christopher J. Eden, Birgit Nimmervoll, Charles A. Lessman, Mohankumar Murugesan, Timothy N. Phoenix, Karen Wright, David W. Ellison |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
medicine.drug_class Transplantation Heterologous Brain tumor Biology Tyrosine-kinase inhibitor Article Mice Glioma Drug Discovery Genetics medicine Animals Humans Child Molecular Biology Zebrafish Brain Neoplasms fungi Choroid plexus carcinoma medicine.disease biology.organism_classification 3. Good health High-Throughput Screening Assays Disease Models Animal Drug development Cancer cell Immunology Cancer research Erlotinib Transcriptome Neoplasm Transplantation medicine.drug |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | High-throughput screens (HTS) of compound toxicity against cancer cells can identify thousands of potential new drug-leads. But only limited numbers of these compounds can progress to expensive and labor intensive efficacy studies in mice, creating a ‘bottle-neck’ in the drug development pipeline. Approaches that triage drug-leads for further study are greatly needed. Here, we provide an intermediary platform between HTS and mice by adapting mouse models of pediatric brain tumors to grow as orthotopic xenografts in the brains of zebrafish. Freshly isolated mouse ependymoma, glioma and choroid plexus carcinoma cells expressing red fluorescence protein (RFP) were conditioned to grow at 34°C. Conditioned tumor cells were then transplanted orthotopically into the brains of zebrafish acclimatized to ambient temperatures of 34°C. Live in vivo fluorescence imaging identified robust, quantifiable and reproducible brain tumor growth as well as spinal metastasis in zebrafish. All tumor xenografts in zebrafish retained the histological characteristics of the corresponding parent mouse tumor and efficiently recruited fish endothelial cells to form a tumor vasculature. Finally, by treating zebrafish harboring ERBB2-driven gliomas with an appropriate cytotoxic chemotherapy (5-fluorouracil) or tyrosine kinase inhibitor (Erlotinib), we show that these models can effectively assess drug efficacy. Our data demonstrate, for the first time, that mouse brain tumors can grow orthtopically in fish and serve as a platform to study drug efficacy. Since large cohorts of brain tumor bearing zebrafish can be generated rapidly and inexpensively, these models may serve as a powerful tool to triage drug-leads from HTS for formal efficacy testing in mice. |
| Databáze: | OpenAIRE |
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