Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation
Abstract A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to det...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01459-9 |
| _version_ | 1797984713777872896 |
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| author | Nelli S. Lakis Alexander S. Brodsky Galina Karashchuk Amanda J. Audesse Dongfang Yang Ashlee Sturtevant Kara Lombardo Ian Y. Wong Ashley E. Webb Douglas C. Anthony |
| author_facet | Nelli S. Lakis Alexander S. Brodsky Galina Karashchuk Amanda J. Audesse Dongfang Yang Ashlee Sturtevant Kara Lombardo Ian Y. Wong Ashley E. Webb Douglas C. Anthony |
| author_sort | Nelli S. Lakis |
| collection | DOAJ |
| description | Abstract A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan–Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment. |
| first_indexed | 2024-04-11T07:07:14Z |
| format | Article |
| id | doaj.art-d5691a8a61b44c2b926561532afe4f88 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-11T07:07:14Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-d5691a8a61b44c2b926561532afe4f882022-12-22T04:38:22ZengBMCActa Neuropathologica Communications2051-59602022-11-0110111510.1186/s40478-022-01459-9Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylationNelli S. Lakis0Alexander S. Brodsky1Galina Karashchuk2Amanda J. Audesse3Dongfang Yang4Ashlee Sturtevant5Kara Lombardo6Ian Y. Wong7Ashley E. Webb8Douglas C. Anthony9Department of Pathology, Kansas University Medical CenterDepartment of Pathology and Laboratory Medicine, Lifespan Academic Medical CenterDepartment of Pathology and Laboratory Medicine, Lifespan Academic Medical CenterDepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown UniversityDepartment of Pathology and Laboratory Medicine, Lifespan Academic Medical CenterDepartment of Pathology and Laboratory Medicine, Lifespan Academic Medical CenterDepartment of Pathology and Laboratory Medicine, Lifespan Academic Medical CenterDepartment of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown UniversityDepartment of Molecular Biology, Cell Biology, and Biochemistry, Brown UniversityDepartment of Pathology and Laboratory Medicine, Lifespan Academic Medical CenterAbstract A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan–Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment.https://doi.org/10.1186/s40478-022-01459-9GlioblastomaCancer stem cellsSOX2CD133MGMT |
| spellingShingle | Nelli S. Lakis Alexander S. Brodsky Galina Karashchuk Amanda J. Audesse Dongfang Yang Ashlee Sturtevant Kara Lombardo Ian Y. Wong Ashley E. Webb Douglas C. Anthony Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation Acta Neuropathologica Communications Glioblastoma Cancer stem cells SOX2 CD133 MGMT |
| title | Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation |
| title_full | Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation |
| title_fullStr | Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation |
| title_full_unstemmed | Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation |
| title_short | Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation |
| title_sort | stem cell phenotype predicts therapeutic response in glioblastomas with mgmt promoter methylation |
| topic | Glioblastoma Cancer stem cells SOX2 CD133 MGMT |
| url | https://doi.org/10.1186/s40478-022-01459-9 |
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