Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma
Abstract Rationale Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis. The U.S. food and drug administration approved the use of the anti-VEGF antibody bevacizumab in recurrent GBM. However, resistance to this treatment is frequent and fails to enhance the overall survival of...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-10-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01451-3 |
| _version_ | 1797991741025943552 |
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| author | Ahmad Joshkon Emeline Tabouret Wael Traboulsi Richard Bachelier Stéphanie Simoncini Sandrine Roffino Carine Jiguet-Jiglaire Bassam Badran Benjamin Guillet Alexandrine Foucault-Bertaud Aurelie S. Leroyer Françoise Dignat-George Olivier Chinot Hussein Fayyad-Kazan Nathalie Bardin Marcel Blot-Chabaud |
| author_facet | Ahmad Joshkon Emeline Tabouret Wael Traboulsi Richard Bachelier Stéphanie Simoncini Sandrine Roffino Carine Jiguet-Jiglaire Bassam Badran Benjamin Guillet Alexandrine Foucault-Bertaud Aurelie S. Leroyer Françoise Dignat-George Olivier Chinot Hussein Fayyad-Kazan Nathalie Bardin Marcel Blot-Chabaud |
| author_sort | Ahmad Joshkon |
| collection | DOAJ |
| description | Abstract Rationale Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis. The U.S. food and drug administration approved the use of the anti-VEGF antibody bevacizumab in recurrent GBM. However, resistance to this treatment is frequent and fails to enhance the overall survival of patients. In this study, we aimed to identify novel mechanism(s) responsible for bevacizumab-resistance in CD146-positive glioblastoma. Methods The study was performed using sera from GBM patients and human GBM cell lines in culture or xenografted in nude mice. Results We found that an increase in sCD146 concentration in sera of GBM patients after the first cycle of bevacizumab treatment was significantly associated with poor progression free survival and shorter overall survival. Accordingly, in vitro treatment of CD146-positive glioblastoma cells with bevacizumab led to a high sCD146 secretion, inducing cell invasion. These effects were mediated through integrin αvβ3 and were blocked by mucizumab, a novel humanized anti-sCD146 antibody. In vivo, the combination of bevacizumab with mucizumab impeded CD146 + glioblastoma growth and reduced tumor cell dissemination to an extent significantly higher than that observed with bevacizumab alone. Conclusion We propose sCD146 to be 1/ an early biomarker to predict and 2/ a potential target to prevent bevacizumab resistance in patients with glioblastoma. |
| first_indexed | 2024-04-11T08:56:13Z |
| format | Article |
| id | doaj.art-4d1eae0ff4d841e7be8d966be7f7fe12 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-11T08:56:13Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-4d1eae0ff4d841e7be8d966be7f7fe122022-12-22T04:33:17ZengBMCActa Neuropathologica Communications2051-59602022-10-0110111210.1186/s40478-022-01451-3Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastomaAhmad Joshkon0Emeline Tabouret1Wael Traboulsi2Richard Bachelier3Stéphanie Simoncini4Sandrine Roffino5Carine Jiguet-Jiglaire6Bassam Badran7Benjamin Guillet8Alexandrine Foucault-Bertaud9Aurelie S. Leroyer10Françoise Dignat-George11Olivier Chinot12Hussein Fayyad-Kazan13Nathalie Bardin14Marcel Blot-Chabaud15Aix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, APHM, CNRS, INP, Service de Neuro-Oncologie CHU TimoneAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, INSERM1263, INRAE1260, C2VNCNRS, ISM UMR 7287, Aix-Marseille UniversityAix-Marseille University, APHM, CNRS, INP, Service de Neuro-Oncologie CHU TimoneLaboratory of Cancer Biology and Molecular Immunology, Faculty of Science, Lebanese UniversityAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, APHM, CNRS, INP, Service de Neuro-Oncologie CHU TimoneLaboratory of Cancer Biology and Molecular Immunology, Faculty of Science, Lebanese UniversityAix-Marseille University, INSERM1263, INRAE1260, C2VNAix-Marseille University, INSERM1263, INRAE1260, C2VNAbstract Rationale Glioblastoma multiforme (GBM) is a primary brain tumor with poor prognosis. The U.S. food and drug administration approved the use of the anti-VEGF antibody bevacizumab in recurrent GBM. However, resistance to this treatment is frequent and fails to enhance the overall survival of patients. In this study, we aimed to identify novel mechanism(s) responsible for bevacizumab-resistance in CD146-positive glioblastoma. Methods The study was performed using sera from GBM patients and human GBM cell lines in culture or xenografted in nude mice. Results We found that an increase in sCD146 concentration in sera of GBM patients after the first cycle of bevacizumab treatment was significantly associated with poor progression free survival and shorter overall survival. Accordingly, in vitro treatment of CD146-positive glioblastoma cells with bevacizumab led to a high sCD146 secretion, inducing cell invasion. These effects were mediated through integrin αvβ3 and were blocked by mucizumab, a novel humanized anti-sCD146 antibody. In vivo, the combination of bevacizumab with mucizumab impeded CD146 + glioblastoma growth and reduced tumor cell dissemination to an extent significantly higher than that observed with bevacizumab alone. Conclusion We propose sCD146 to be 1/ an early biomarker to predict and 2/ a potential target to prevent bevacizumab resistance in patients with glioblastoma.https://doi.org/10.1186/s40478-022-01451-3Soluble CD146BiomarkerTherapeutic antibodyBevacizumabGlioblastoma |
| spellingShingle | Ahmad Joshkon Emeline Tabouret Wael Traboulsi Richard Bachelier Stéphanie Simoncini Sandrine Roffino Carine Jiguet-Jiglaire Bassam Badran Benjamin Guillet Alexandrine Foucault-Bertaud Aurelie S. Leroyer Françoise Dignat-George Olivier Chinot Hussein Fayyad-Kazan Nathalie Bardin Marcel Blot-Chabaud Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma Acta Neuropathologica Communications Soluble CD146 Biomarker Therapeutic antibody Bevacizumab Glioblastoma |
| title | Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma |
| title_full | Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma |
| title_fullStr | Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma |
| title_full_unstemmed | Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma |
| title_short | Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma |
| title_sort | soluble cd146 a biomarker and a target for preventing resistance to anti angiogenic therapy in glioblastoma |
| topic | Soluble CD146 Biomarker Therapeutic antibody Bevacizumab Glioblastoma |
| url | https://doi.org/10.1186/s40478-022-01451-3 |
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