Journal article
Radiation-Induced DNA Damage Cooperates with Heterozygosity of TP53 and PTEN to Generate High-Grade Gliomas
Cancer research (Chicago, Ill.), Vol.79(14), pp.3749-3761
07/15/2019
DOI: 10.1158/0008-5472.CAN-19-0680
PMCID: PMC6635038
PMID: 31088835
Abstract
Glioblastomas are lethal brain tumors that are treated with conventional radiation (X-rays and gamma rays) or particle radiation (protons and carbon ions). Paradoxically, radiation is also a risk factor for GBM development, raising the possibility that radiotherapy of brain tumors could promote tumor recurrence or trigger secondary gliomas. In this study, we determined whether tumor suppressor losses commonly displayed by patients with GBM confer susceptibility to radiation-induced glioma. Mice with Nestin-Cre-driven deletions of
and
alleles were intracranially irradiated with X-rays or charged particles of increasing atomic number and linear energy transfer (LET). Mice with loss of one allele each of
and
did not develop spontaneous gliomas, but were highly susceptible to radiation-induced gliomagenesis. Tumor development frequency after exposure to high-LET particle radiation was significantly higher compared with X-rays, in accordance with the irreparability of DNA double-strand breaks (DSB) induced by high-LET radiation. All resultant gliomas, regardless of radiation quality, presented histopathologic features of grade IV lesions and harbored populations of cancer stem-like cells with tumor-propagating properties. Furthermore, all tumors displayed concomitant loss of heterozygosity of
and
along with frequent amplification of the
receptor tyrosine kinase, which conferred a stem cell phenotype to tumor cells. Our results demonstrate that radiation-induced DSBs cooperate with preexisting tumor suppressor losses to generate high-grade gliomas. Moreover, our mouse model can be used for studies on radiation-induced development of GBM and therapeutic strategies. SIGNIFICANCE: This study uncovers mechanisms by which ionizing radiation, especially particle radiation, promote GBM development or recurrence.
Details
- Title: Subtitle
- Radiation-Induced DNA Damage Cooperates with Heterozygosity of TP53 and PTEN to Generate High-Grade Gliomas
- Creators
- Pavlina K Todorova - The University of Texas Southwestern Medical CenterEliot Fletcher-Sananikone - The University of Texas Southwestern Medical CenterBipasha Mukherjee - The University of Texas Southwestern Medical CenterRahul Kollipara - Southwestern Medical CenterVamsidhara Vemireddy - The University of Texas Southwestern Medical CenterXian-Jin Xie - University of IowaPeter M Guida - Brookhaven National LaboratoryMichael D Story - The University of Texas Southwestern Medical CenterKimmo Hatanpaa - The University of Texas Southwestern Medical CenterAmyn A Habib - The University of Texas Southwestern Medical CenterRalf Kittler - Southwestern Medical CenterRobert Bachoo - The University of Texas Southwestern Medical CenterRobert Hromas - The University of Texas at AustinJohn R Floyd - Department of Neurosurgery, University of Texas Health, San Antonio, TexasSandeep Burma - The University of Texas at Austin
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.79(14), pp.3749-3761
- DOI
- 10.1158/0008-5472.CAN-19-0680
- PMID
- 31088835
- PMCID
- PMC6635038
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- R01 CA197796 / NCI NIH HHS R01 GM109645 / NIGMS NIH HHS R01 CA149461 / NCI NIH HHS R01 CA205224 / NCI NIH HHS
- Language
- English
- Date published
- 07/15/2019
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9984367647502771
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