Establishment of atypical-teratoid/rhabdoid tumor (AT/RT) cell cultures from disseminated CSF cells: a model to elucidate biology and potential targeted therapeutics
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Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects infants and young children. In this report, we describe culture conditions that enabled the sustained growth of tumor cells obtained from the cerebrospinal fluid (CSF) of an infant with AT/RT. These cells retained the morphological and biomarker characteristics of the original tumor. A screening of receptor tyrosine kinases identified the presence of phosphorylated ErbB4, Insulin-R, PDGFR and IGF-IR, which appear to depend on Hsp90 to maintain their active form. IGF-IR activity is consistent with data from other established AT/RT cell lines. Inhibition of IGF-IR by the small molecular weight inhibitor AEW541 led to growth suppression of cultured AT/RT cells. In addition, neutralizing antibodies to IGF-II also inhibited the growth of these cells suggesting a potential autocrine function for this cytokine. We also compared cultured AT/RT cells to established cell lines to identify consistent drug sensitivity patterns among these cells. In addition to previously described cell lines and xenograft models, continuous culture of CSF derived cells may also provide an effective way to study the biology of AT/RT and to identify potential targets for future therapeutics for this tumor.
KeywordsAtypical-teratoid/rhabdoid tumor ATRT Cell culture IGF-IR
This work was supported in part by the Kids Cancer Care Foundation of Alberta (KCCF), for which the cell line was named. Additional research funding was provided by the Brain Tumor Research Foundation of Canada. We acknowledge the Oncology Pharmacy at the Alberta Children’s Hospital for providing many of the anti-neoplastic agents used in our experiments.
- 3.Biegel JA, Fogelgren B, Wainwright LM (2000) Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and a renal rhabdoid tumor. Genes Chromosomes Cancer 28:31–37. doi :10.1002/(SICI)1098-2264(200005)28:1<31::AID-GCC4>3.0.CO;2-YGoogle Scholar
- 9.Kohashi K, Oda Y, Yamamoto H et al (2007) Highly aggressive behavior of malignant rhabdoid tumor: a special reference to SMARCB1/INI1 gene alterations using molecular genetic analysis including quantitative real-time PCR. J Cancer Res Clin Oncol 133(11):817–824. doi: 10.1007/s00432-007-0223-z PubMedCrossRefGoogle Scholar
- 18.Narendran A, Hawkins L (2004) Studies using 17-allylamino-17-demethoxygeldanamycin (17-AAG) to understand the heterogeneity of Hsp90 linked survival and signalling pathways in neuroblastoma ANR meeting, Genoa. http://www.anrmeeting.org/anr2004-abstracts/N/396.1%20Narendran.doc
- 23.Maris JM, Courtright J, Houghton PJ et al (2008) Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatr Blood Cancer 2008(Feb):21 (Epub ahead of print)Google Scholar
- 25.Hawkins LM, Jayanthan AA, Narendran A (2005) Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. Pediatr Res 57(3):430–437. doi: 10.1203/01.PDR.0000153871.45184.19 PubMedCrossRefGoogle Scholar
- 33.Lu L, Wilkinson EJ, Yachnis AT (2000) CSF cytology of atypical teratoid/rhabdoid tumor of the brain in a two-year-old girl: a case report. Diagn Cytopathol 23(5):329–332. doi :10.1002/1097-0339(200011)23:5<329::AID-DC9>3.0.CO;2-WGoogle Scholar