Morphologic and molecular characterization of ATRT xenografts adapted for orthotopic therapeutic testing

Rintaro Hashizume, Nalin Gupta, Mitchel S. Berger, Anu Banerjee, Michael D. Prados, Jennifer Ayers-Ringler, C. David James, Scott R. VandenBerg

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Atypical teratoid rhabdoid tumor (ATRT) is a malignant tumor of the central nervous system that most commonly arises in young children. The aggressive growth and propensity for early dissemination throughout the neuraxis confers a dismal prognosis. Large clinical trials that could test new therapeutic agents are difficult to conduct due to the low incidence of this cancer. For this reason, high throughput preclinical testing with suitable animal models for ATRT would serve a critical need for identifying the most efficacious treatments. In response to this need, we have adapted ATRT cell lines for bioluminescence imaging (BLI) of intracranial (orthotopic) xenografts established in athymic mice. Our results indicate that following supratentorial or infratentorial injection in athymic mice, ATRT cells produce rapidly growing tumors, often with intraventricular spread or neuraxis dissemination. When established as orthotopic xenografts, the tumors predominantly display cells with a rhabdoid-like cellular morphology that show a spectrum of immunophenotypes similar to primary ATRT tumors. To demonstrate the feasibility of this orthotopic ATRT xenograft model for therapeutic testing with correlation to biomarker analysis, we examined the responses of luciferase-modified ATRT cells to temozolomide (TMZ). These xenografts, which highly express MGMT, are resistant to TMZ treatment when compared with an orthotopic glioblastoma xenograft that is MGMT deficient and responsive to TMZ. These data suggest that an orthotopic ATRT xenograft model, in which BLI is used for monitoring tumor growth and response to therapy, should contribute to the identification of effective therapeutics and regimens for treating this highly aggressive pediatric brain tumor.

Original languageEnglish (US)
Pages (from-to)366-376
Number of pages11
JournalNeuro-oncology
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2010

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Keywords

  • Atypical teratoid rhabdoid tumor
  • Bioluminescence
  • INI1
  • Orthotopic
  • Xenograft

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Hashizume, R., Gupta, N., Berger, M. S., Banerjee, A., Prados, M. D., Ayers-Ringler, J., James, C. D., & VandenBerg, S. R. (2010). Morphologic and molecular characterization of ATRT xenografts adapted for orthotopic therapeutic testing. Neuro-oncology, 12(4), 366-376. https://doi.org/10.1093/neuonc/nop033