Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease
Abstract Diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma (HGG) affecting young children, has the highest mortality rate of all pediatric cancers. Despite treatment, average survival is less than twelve months, and five-year survival under 5%. We previously detected increa...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0727-1 |
| _version_ | 1819082386529320960 |
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| author | J. Qi D. R. Esfahani T. Huang P. Ozark E. Bartom R. Hashizume E. R. Bonner S. An C. M. Horbinski C. D. James A. M. Saratsis |
| author_facet | J. Qi D. R. Esfahani T. Huang P. Ozark E. Bartom R. Hashizume E. R. Bonner S. An C. M. Horbinski C. D. James A. M. Saratsis |
| author_sort | J. Qi |
| collection | DOAJ |
| description | Abstract Diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma (HGG) affecting young children, has the highest mortality rate of all pediatric cancers. Despite treatment, average survival is less than twelve months, and five-year survival under 5%. We previously detected increased expression of Tenascin-C (TNC) protein in DIPG cerebrospinal fluid and tumor tissue relative to normal specimens. TNC is an extracellular matrix (ECM) glycoprotein that mediates cell-matrix interactions, guides migrating neurons during normal brain development and is thought to maintain the periventricular stem cell niche in the developing brain. Tumor TNC expression is reported in adult glioma and other cancers. However, the pattern and effects of TNC expression in DIPG has not been previously explored. Here, we characterize TNC expression in patient derived pediatric supratentorial HGG (n = 3) and DIPG (n = 6) cell lines, as well as pediatric glioma tumor (n = 50) and normal brain tissue specimens (n = 3). We found tumor specific TNC gene and protein overexpression that directly correlated with higher tumor grade (WHO III and IV, p = 0.05), H3K27 M mutation (p = 0.012), shorter progression free survival (p = 0.034), and poorer overall survival (0.041) in association with these factors. TNC knockdown via lentiviral shRNA transfection of HGG (n = 1) and DIPG (n = 3) cell lines resulted in decreased cell proliferation, migration, and invasion in vitro (p < 0.01), while TNC cDNA transfection resulted in increased cell migration, invasion and proliferation (p < 0.01) as well as altered cell morphology in H3K27 M mutant DIPG lines. Whole transcriptome sequencing analysis (RNA-Seq) on DIPG (n = 3) and HGG (n = 2) cell lines after TNC cDNA, shRNA, and empty vector control transfection revealed the effects of TNC expression level on global gene expression profiles. Together, our findings reveal TNC expression in DIPG in association with H3K27 M mutation and VEGF signaling, and suggest that TNC may contribute to DIPG tumor phenotype, and serve as a clinically detectable biomarker for DIPG. |
| first_indexed | 2024-12-21T20:15:51Z |
| format | Article |
| id | doaj.art-da02665ac49c44e09a275ad3632073ee |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-21T20:15:51Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-da02665ac49c44e09a275ad3632073ee2022-12-21T18:51:37ZengBMCActa Neuropathologica Communications2051-59602019-05-017111910.1186/s40478-019-0727-1Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of diseaseJ. Qi0D. R. Esfahani1T. Huang2P. Ozark3E. Bartom4R. Hashizume5E. R. Bonner6S. An7C. M. Horbinski8C. D. James9A. M. Saratsis10Department of Neurological Surgery, Northwestern University Feinberg School of MedicineDepartment of Neurological Surgery, University of Illinois at ChicagoDepartment of Neurological Surgery, Northwestern University Feinberg School of MedicineDepartment of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of MedicineDepartment of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of MedicineDepartment of Neurological Surgery, Northwestern University Feinberg School of MedicineCenter for Genetic Medicine, Children’s National Health SystemDepartment of Neurological Surgery, Northwestern University Feinberg School of MedicineDepartment of Neurological Surgery, Northwestern University Feinberg School of MedicineDepartment of Neurological Surgery, Northwestern University Feinberg School of MedicineDepartment of Neurological Surgery, Northwestern University Feinberg School of MedicineAbstract Diffuse intrinsic pontine glioma (DIPG), an infiltrative, high grade glioma (HGG) affecting young children, has the highest mortality rate of all pediatric cancers. Despite treatment, average survival is less than twelve months, and five-year survival under 5%. We previously detected increased expression of Tenascin-C (TNC) protein in DIPG cerebrospinal fluid and tumor tissue relative to normal specimens. TNC is an extracellular matrix (ECM) glycoprotein that mediates cell-matrix interactions, guides migrating neurons during normal brain development and is thought to maintain the periventricular stem cell niche in the developing brain. Tumor TNC expression is reported in adult glioma and other cancers. However, the pattern and effects of TNC expression in DIPG has not been previously explored. Here, we characterize TNC expression in patient derived pediatric supratentorial HGG (n = 3) and DIPG (n = 6) cell lines, as well as pediatric glioma tumor (n = 50) and normal brain tissue specimens (n = 3). We found tumor specific TNC gene and protein overexpression that directly correlated with higher tumor grade (WHO III and IV, p = 0.05), H3K27 M mutation (p = 0.012), shorter progression free survival (p = 0.034), and poorer overall survival (0.041) in association with these factors. TNC knockdown via lentiviral shRNA transfection of HGG (n = 1) and DIPG (n = 3) cell lines resulted in decreased cell proliferation, migration, and invasion in vitro (p < 0.01), while TNC cDNA transfection resulted in increased cell migration, invasion and proliferation (p < 0.01) as well as altered cell morphology in H3K27 M mutant DIPG lines. Whole transcriptome sequencing analysis (RNA-Seq) on DIPG (n = 3) and HGG (n = 2) cell lines after TNC cDNA, shRNA, and empty vector control transfection revealed the effects of TNC expression level on global gene expression profiles. Together, our findings reveal TNC expression in DIPG in association with H3K27 M mutation and VEGF signaling, and suggest that TNC may contribute to DIPG tumor phenotype, and serve as a clinically detectable biomarker for DIPG.http://link.springer.com/article/10.1186/s40478-019-0727-1Tenascin-CDiffuse midline gliomaDiffuse intrinsic pontine glioma (DIPG)Histone H3 mutation (H3K27 M) |
| spellingShingle | J. Qi D. R. Esfahani T. Huang P. Ozark E. Bartom R. Hashizume E. R. Bonner S. An C. M. Horbinski C. D. James A. M. Saratsis Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease Acta Neuropathologica Communications Tenascin-C Diffuse midline glioma Diffuse intrinsic pontine glioma (DIPG) Histone H3 mutation (H3K27 M) |
| title | Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease |
| title_full | Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease |
| title_fullStr | Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease |
| title_full_unstemmed | Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease |
| title_short | Tenascin-C expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease |
| title_sort | tenascin c expression contributes to pediatric brainstem glioma tumor phenotype and represents a novel biomarker of disease |
| topic | Tenascin-C Diffuse midline glioma Diffuse intrinsic pontine glioma (DIPG) Histone H3 mutation (H3K27 M) |
| url | http://link.springer.com/article/10.1186/s40478-019-0727-1 |
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