Abstract
Diffuse intrinsic pontine gliomas arise almost exclusively in children, and despite advances in treatment, the majority of patients die within 2 years after initial diagnosis. Because of their infiltrative nature and anatomic location in an eloquent area of the brain, most pontine gliomas are treated without a surgical biopsy. The corresponding lack of tissue samples has resulted in a limited understanding of the underlying genetic and molecular biologic abnormalities associated with pontine gliomas, and is a substantial obstacle for the preclinical testing of targeted therapeutic agents for these tumors. We have established a human glioma cell line that originated from surgical biopsy performed on a patient with a pontine glioma. To insure sustainable in vitro propagation, tumor cells were modified with hTERT (human telomerase ribonucleoprotein reverse transcriptase), and with a luciferase reporter to enable non-invasive bioluminescence imaging. The hTERT modified cells are tumorigenic in athymic rodents, and produce brainstem tumors that recapitulate the infiltrative growth of brainstem gliomas in patients.
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Donaldson SS, Laningham F, Fisher PG (2006) Advances toward an understanding of brainstem gliomas. J Clin Oncol 24(8):1266–1272. doi:10.1200/JCO.2005.04.6599
Recinos PF, Sciubba DM, Jallo GI (2007) Brainstem tumors: where are we today? Pediatr Neurosurg 43(3):192–201. doi:10.1159/000098831
Finlay JL, Zacharoulis S (2005) The treatment of high grade gliomas and diffuse intrinsic pontine tumors of childhood and adolescence: a historical - and futuristic -perspective. J Neurooncol 75(3):253–266. doi:10.1007/s11060-005-6747-7
Sharp JR, Bouffet E, Stempak D, Gammon J, Stephens D, Johnston DL, Eisenstat D, Hukin J, Samson Y, Bartels U, Tabori U, Huang A, Baruchel S (2010) A multi-centre Canadian pilot study of metronomic temozolomide combined with radiotherapy for newly diagnosed paediatric brainstem glioma. Eur J Cancer 46(18):3271–3279. doi:10.1016/j.ejca.2010.06.115
Huse JT, Phillips HS, Brennan CW (2011) Molecular subclassification of diffuse gliomas: seeing order in the chaos. Glia 59(8):1190–1199. doi:10.1002/glia.21165
Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9(3):157–173. doi:10.1016/j.ccr.2006.02.019
Paugh BS, Broniscer A, Qu C, Miller CP, Zhang J, Tatevossian RG, Olson JM, Geyer JR, Chi SN, da Silva NS, Onar-Thomas A, Baker JN, Gajjar A, Ellison DW, Baker SJ (2011) Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29(30):3999–4006. doi:10.1200/JCO.2011.35.5677
Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, Zhang J, Gajjar A, Dyer MA, Mullighan CG, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Ellison DW, Baker SJ (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet. doi:10.1038/ng.1102
Aoki Y, Hashizume R, Ozawa T, Banerjee A, Prados M, James CD, Gupta N (2012) An experimental xenograft mouse model of diffuse pontine glioma designed for therapeutic testing. J Neurooncol. doi:10.1007/s11060-011-0796-x
Hashizume R, Ozawa T, Dinca EB, Banerjee A, Prados MD, James CD, Gupta N (2010) A human brainstem glioma xenograft model enabled for bioluminescence imaging. J Neurooncol 96(2):151–159. doi:10.1007/s11060-009-9954-9
Caretti V, Zondervan I, Meijer DH, Idema S, Vos W, Hamans B, Bugiani M, Hulleman E, Wesseling P, Vandertop WP, Noske DP, Kaspers G, Molthoff CF, Wurdinger T (2010) Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model. Brain Pathol. doi:10.1111/j.1750-3639.2010.00468.x
Monje M, Mitra SS, Freret ME, Raveh TB, Kim J, Masek M, Attema JL, Li G, Haddix T, Edwards MS, Fisher PG, Weissman IL, Rowitch DH, Vogel H, Wong AJ, Beachy PA (2011) Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc Natl Acad Sci U S A 108(11):4453–4458. doi:10.1073/pnas.1101657108
Sanai N, Wachhorst SP, Gupta NM, McDermott MW (2008) Transcerebellar stereotactic biopsy for lesions of the brainstem and peduncles under local anesthesia. Neurosurgery 63(3):460–466; discussion 466–468. doi:10.1227/01.NEU.0000324731.68843.74
Gunther HS, Schmidt NO, Phillips HS, Kemming D, Kharbanda S, Soriano R, Modrusan Z, Meissner H, Westphal M, Lamszus K (2008) Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria. Oncogene 27(20):2897–2909. doi:10.1038/sj.onc.1210949
Dinca EB, Sarkaria JN, Schroeder MA, Carlson BL, Voicu R, Gupta N, Berger MS, James CD (2007) Bioluminescence monitoring of intracranial glioblastoma xenograft: response to primary and salvage temozolomide therapy. J Neurosurg 107(3):610–616. doi:10.3171/JNS-07/09/0610
Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF, Hakonarson H, Bucan M (2007) PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 17(11):1665–1674. doi:10.1101/gr.6861907
Paugh BS, Qu C, Jones C, Liu Z, Adamowicz-Brice M, Zhang J, Bax DA, Coyle B, Barrow J, Hargrave D, Lowe J, Gajjar A, Zhao W, Broniscer A, Ellison DW, Grundy RG, Baker SJ (2010) Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28(18):3061–3068. doi:10.1200/JCO.2009.26.7252
Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D, Pounds SB, Rand V, Leary SE, White E, Eden C, Hogg T, Northcott P, Mack S, Neale G, Wang YD, Coyle B, Atkinson J, DeWire M, Kranenburg TA, Gillespie Y, Allen JC, Merchant T, Boop FA, Sanford RA, Gajjar A, Ellison DW, Taylor MD, Grundy RG, Gilbertson RJ (2010) Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466(7306):632–636. doi:10.1038/nature09173
Zarghooni M, Bartels U, Lee E, Buczkowicz P, Morrison A, Huang A, Bouffet E, Hawkins C (2010) Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28(8):1337–1344. doi:10.1200/JCO.2009.25.5463
Becher OJ, Hambardzumyan D, Walker TR, Helmy K, Nazarian J, Albrecht S, Hiner RL, Gall S, Huse JT, Jabado N, MacDonald TJ, Holland EC (2010) Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma. Cancer Res 70(6):2548–2557. doi:10.1158/0008-5472.CAN-09-2503
Masui K, Suzuki SO, Torisu R, Goldman JE, Canoll P, Iwaki T (2010) Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation. Glia 58(9):1050–1065. doi:10.1002/glia.20986
Wen VW, Wu K, Baksh S, Hinshelwood RA, Lock RB, Clark SJ, Moore MA, Mackenzie KL (2006) Telomere-driven karyotypic complexity concurs with p16INK4a inactivation in TP53-competent immortal endothelial cells. Cancer Res 66(22):10691–10700. doi:10.1158/0008-5472.CAN-06-0979
Acknowledgments
This study was supported by the Pediatric Brain Tumor Foundation Institute Award to the University of California San Francisco, and Timmy’s Rainbow Foundation for Brainstem Tumor Research. The authors also thank Dr. Susan Baker (St. Jude’s Children’s Hospital and Medical Center) for allowing permission to examine copy number data from a published data set of pediatric astrocytic tumors.
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Hashizume, R., Smirnov, I., Liu, S. et al. Characterization of a diffuse intrinsic pontine glioma cell line: implications for future investigations and treatment. J Neurooncol 110, 305–313 (2012). https://doi.org/10.1007/s11060-012-0973-6
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DOI: https://doi.org/10.1007/s11060-012-0973-6