Precision Medicine with TGF-β Inhibition Using Tumor Explants: Comment on 'Patient-Specific Screening Using High-Grade Glioma Explants to Determine Potential Radiosensitization by a TGF-β Small Molecule Inhibitor' by N. Sumru Bayin et al
| Autor: | Haidong Huang, Jennifer S. Yu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Original article Cancer Research Brain Neoplasms Glioma Transforming growth factor beta Biology medicine.disease Small molecule Molecular biology 03 medical and health sciences 030104 developmental biology Transforming Growth Factor beta biology.protein medicine Humans Precision Medicine Signal transduction Receptor Receptors Transforming Growth Factor beta Ex vivo Signal Transduction Explant culture 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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