Inhibiting Integrin β8 to Differentiate and Radiosensitize Glioblastoma-Initiating Cells
| Autor: | Christine Toulas, Aline Kowalski-Chauvel, Anthony Lemarié, Dina Ferreira Da Mota, Elizabeth Cohen-Jonathan Moyal, Solène M. Evrard, Julia Gilhodes, Laure Malric, Thomas Filleron, Sabrina Boyrie, Perrine Dahan, Aurore Siegfried, Caroline Delmas, Sylvie Monferran, Florent Arnauduc, Pauline Deshors, Vincent Lubrano |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Radiation-Sensitizing Agents Integrin beta Chains medicine.medical_treatment Cellular differentiation Integrin Mice Nude Stem cell marker Transfection 03 medical and health sciences Mice 0302 clinical medicine Medicine Animals Humans Viability assay ITGB8 Molecular Biology biology business.industry Brain Neoplasms Cell Differentiation Radiation therapy 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research business Glioblastoma |
| Zdroj: | Molecular cancer research : MCR. 17(2) |
| ISSN: | 1557-3125 |
| Popis: | Glioblastomas (GB) are malignant brain tumors with poor prognosis despite treatment with surgery and radio/chemotherapy. These tumors are defined by an important cellular heterogeneity and notably contain a subpopulation of GB-initiating cells (GIC), which contribute to tumor aggressiveness, resistance, and recurrence. Some integrins are specifically expressed by GICs and could be actionable targets to improve GB treatment. Here, integrin β8 (ITGB8) was identified as a potential selective target in this highly tumorigenic GIC subpopulation. Using several patient-derived primocultures, it was demonstrated that ITGB8 is overexpressed in GICs compared with their differentiated progeny. Furthermore, ITGB8 is also overexpressed in GB, and its overexpression is correlated with poor prognosis and with the expression of several other classic stem cell markers. Moreover, inhibiting ITGB8 diminished several main GIC characteristics and features, including self-renewal ability, stemness, migration potential, and tumor formation capacity. Blockade of ITGB8 significantly impaired GIC cell viability via apoptosis induction. Finally, the combination of radiotherapy and ITGB8 targeting radiosensitized GICs through postmitotic cell death. Implications: This study identifies ITGB8 as a new selective marker for GICs and as a promising therapeutic target in combination with chemo/radiotherapy for the treatment of highly aggressive brain tumors. |
| Databáze: | OpenAIRE |
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