Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone
Abstract Background Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-07-01
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| Series: | Fluids and Barriers of the CNS |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12987-022-00354-8 |
| _version_ | 1811293835418927104 |
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| author | Emily S. Norton Lauren A. Whaley María José Ulloa-Navas Patricia García-Tárraga Kayleah M. Meneses Montserrat Lara-Velazquez Natanael Zarco Anna Carrano Alfredo Quiñones-Hinojosa José Manuel García-Verdugo Hugo Guerrero-Cázares |
| author_facet | Emily S. Norton Lauren A. Whaley María José Ulloa-Navas Patricia García-Tárraga Kayleah M. Meneses Montserrat Lara-Velazquez Natanael Zarco Anna Carrano Alfredo Quiñones-Hinojosa José Manuel García-Verdugo Hugo Guerrero-Cázares |
| author_sort | Emily S. Norton |
| collection | DOAJ |
| description | Abstract Background Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and increased incidence of distal tumor recurrence. This may be due in part to interaction of GBM with factors of the subventricular zone (SVZ), including those contained within the cerebrospinal fluid (CSF). However, direct interaction of GBM tumors with CSF has not been proved and would be hindered in the presence of an intact ependymal cell layer. Methods Here, we investigate the ependymal cell barrier and its derived extracellular matrix (ECM) fractones in the vicinity of a GBM tumor. Patient-derived GBM cells were orthotopically implanted into immunosuppressed athymic mice in locations distal and proximal to the LV. A PBS vehicle injection in the proximal location was included as a control. At four weeks post-xenograft, brain tissue was examined for alterations in ependymal cell health via immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. Results We identified local invading GBM cells within the LV wall and increased influx of CSF into the LV-proximal GBM tumor bulk compared to controls. In addition to the physical disruption of the ependymal cell barrier, we also identified increased signs of compromised ependymal cell health in LV-proximal tumor-bearing mice. These signs include increased accumulation of lipid droplets, decreased cilia length and number, and decreased expression of cell channel proteins. We additionally identified elevated numbers of small fractones in the SVZ within this group, suggesting increased indirect CSF-contained molecule signaling to tumor cells. Conclusions Our data is the first to show that LV-proximal GBMs physically disrupt the ependymal cell barrier in animal models, resulting in disruptions in ependymal cell biology and increased CSF interaction with the tumor bulk. These findings point to ependymal cell health and CSF-contained molecules as potential axes for therapeutic targeting in the treatment of GBM. |
| first_indexed | 2024-04-13T05:08:28Z |
| format | Article |
| id | doaj.art-9cadd866c9ba4321b8612168ad7dad64 |
| institution | Directory Open Access Journal |
| issn | 2045-8118 |
| language | English |
| last_indexed | 2024-04-13T05:08:28Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Fluids and Barriers of the CNS |
| spelling | doaj.art-9cadd866c9ba4321b8612168ad7dad642022-12-22T03:01:07ZengBMCFluids and Barriers of the CNS2045-81182022-07-0119111510.1186/s12987-022-00354-8Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zoneEmily S. Norton0Lauren A. Whaley1María José Ulloa-Navas2Patricia García-Tárraga3Kayleah M. Meneses4Montserrat Lara-Velazquez5Natanael Zarco6Anna Carrano7Alfredo Quiñones-Hinojosa8José Manuel García-Verdugo9Hugo Guerrero-Cázares10Department of Neurosurgery, Mayo Clinic FloridaDepartment of Neurosurgery, Mayo Clinic FloridaLaboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNEDLaboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNEDDepartment of Cancer Biology, Mayo ClinicDepartment of Neurosurgery, Mayo Clinic FloridaDepartment of Neurosurgery, Mayo Clinic FloridaDepartment of Neurosurgery, Mayo Clinic FloridaDepartment of Neurosurgery, Mayo Clinic FloridaLaboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNEDDepartment of Neurosurgery, Mayo Clinic FloridaAbstract Background Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and increased incidence of distal tumor recurrence. This may be due in part to interaction of GBM with factors of the subventricular zone (SVZ), including those contained within the cerebrospinal fluid (CSF). However, direct interaction of GBM tumors with CSF has not been proved and would be hindered in the presence of an intact ependymal cell layer. Methods Here, we investigate the ependymal cell barrier and its derived extracellular matrix (ECM) fractones in the vicinity of a GBM tumor. Patient-derived GBM cells were orthotopically implanted into immunosuppressed athymic mice in locations distal and proximal to the LV. A PBS vehicle injection in the proximal location was included as a control. At four weeks post-xenograft, brain tissue was examined for alterations in ependymal cell health via immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. Results We identified local invading GBM cells within the LV wall and increased influx of CSF into the LV-proximal GBM tumor bulk compared to controls. In addition to the physical disruption of the ependymal cell barrier, we also identified increased signs of compromised ependymal cell health in LV-proximal tumor-bearing mice. These signs include increased accumulation of lipid droplets, decreased cilia length and number, and decreased expression of cell channel proteins. We additionally identified elevated numbers of small fractones in the SVZ within this group, suggesting increased indirect CSF-contained molecule signaling to tumor cells. Conclusions Our data is the first to show that LV-proximal GBMs physically disrupt the ependymal cell barrier in animal models, resulting in disruptions in ependymal cell biology and increased CSF interaction with the tumor bulk. These findings point to ependymal cell health and CSF-contained molecules as potential axes for therapeutic targeting in the treatment of GBM.https://doi.org/10.1186/s12987-022-00354-8Lateral ventricleStem cell nicheSubependymal zoneGliomaCerebrospinal fluid (CSF)Lipid droplets |
| spellingShingle | Emily S. Norton Lauren A. Whaley María José Ulloa-Navas Patricia García-Tárraga Kayleah M. Meneses Montserrat Lara-Velazquez Natanael Zarco Anna Carrano Alfredo Quiñones-Hinojosa José Manuel García-Verdugo Hugo Guerrero-Cázares Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone Fluids and Barriers of the CNS Lateral ventricle Stem cell niche Subependymal zone Glioma Cerebrospinal fluid (CSF) Lipid droplets |
| title | Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone |
| title_full | Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone |
| title_fullStr | Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone |
| title_full_unstemmed | Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone |
| title_short | Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone |
| title_sort | glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone |
| topic | Lateral ventricle Stem cell niche Subependymal zone Glioma Cerebrospinal fluid (CSF) Lipid droplets |
| url | https://doi.org/10.1186/s12987-022-00354-8 |
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