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Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway.
- Source :
-
Cancer research [Cancer Res] 2016 Jun 01; Vol. 76 (11), pp. 3211-23. Date of Electronic Publication: 2016 Apr 13. - Publication Year :
- 2016
-
Abstract
- While treatments that induce DNA damage are commonly used as anticancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiotherapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine whether the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that Trp53 (p53) was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies, because they retain apoptosis competence. Cancer Res; 76(11); 3211-23. ©2016 AACR.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Blotting, Western
Cell Proliferation
Cerebellar Neoplasms genetics
Cerebellar Neoplasms radiotherapy
Gamma Rays
Medulloblastoma genetics
Medulloblastoma radiotherapy
Mice
RNA, Messenger genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Tumor Cells, Cultured
Apoptosis radiation effects
Cerebellar Neoplasms pathology
Disease Models, Animal
Medulloblastoma pathology
Radiation Tolerance genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 76
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 27197166
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-15-0025