Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor
| Autor: | Donato Pacione, Lin Ma, Dimitris G. Placantonakis, Kush Fansiwala, John G. Golfinos, Mark Bustoros, Matija Snuderl, Mary Helen Barcellos-Hoff, Rabaa Baitalmal, Akhila Sure, N. Sumru Bayin, David Zagzag, Cheddhi Thomas |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Radiation-Sensitizing Agents Cancer Research Radiosensitizer medicine.medical_treatment Antineoplastic Agents Smad2 Protein In Vitro Techniques Biology Stem cell marker Radiation Tolerance 03 medical and health sciences SOX2 Transforming Growth Factor beta Radioresistance Glioma Databases Genetic medicine Humans Precision Medicine Gene Expression Profiling SOXB1 Transcription Factors X-Rays medicine.disease Immunohistochemistry Molecular biology 3. Good health 030104 developmental biology Cytokine Commentary Neoplasm Grading Stem cell DNA Damage Signal Transduction Transforming growth factor |
| Zdroj: | Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-β (TGF-β) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-β signaling, indicated variable levels of TGF-β pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-β during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-β type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of γ-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-β signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients. |
| Databáze: | OpenAIRE |
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