Subventricular zone–associated glioblastoma: A call for translational research to guide clinical decision making

Smith, Andrew W.; Parashar, Bhupesh; Wernicke, A. Gabriella

doi:10.1080/23262133.2016.1225548

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…The SVZ niche in glioblastoma patients may become a therapeutic target in the future whether by radiating the SVZ or by targeting specific components of the SVZ microenvironment [5,18]. We join the call already made by to increase translational and basic research on the SVZ and its role in glioblastoma [23].…”

Section: Discussionmentioning

confidence: 90%

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival

et al. 2020

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Background: Several studies show that subventricular zone (SVZ) contact of glioblastoma at diagnosis is a negative prognosticator of survival. In this report, we study glioblastoma patient survival, molecular biological and MRI-based volumetric findings according to SVZ contact. Patients and methods: We conducted a retrospective study of adult patients diagnosed with supratentorial glioblastoma and uniformly treated with temozolomide-based chemoradiotherapy after surgery. The patient cohort was dichotomized according to tumor contact with the SVZ at diagnosis as determined on preoperative MR imaging. Tumor volume was measured using semi-automated segmentation technique. MGMT-gene promoter methylation and IDH mutation status were determined on stored tumor tissue. Kaplan-Meier survival curves were constructed. Cox regression analysis was used to adjust for known confounding factors of glioblastoma patient survival. Results: A total of 214 patients were included in the study of whom 68% belonged to the SVZ pos group. Median tumor volume was significantly larger in the SVZ pos group (33,8 mL vs 15,6 mL; p < .001). MGMT-unmethylated glioblastoma was more frequent in the SVZ pos group (61.4% vs 44.9%; p ¼ .028). The overall survival and progression-free survival were 12.2 months and 5.9 months for the SVZ pos patient group but 16.9 months and 10.3 months for the SVZ neg group (log-rank p ¼ .016 and .007 respectively). In multivariate Cox survival analysis, SVZ contact proved a negative prognostic parameter, independent from age, KPS, extent of resection, MGMT-methylation and IDH mutation status. Conclusions: This study confirms SVZ contact at diagnosis as an independent negative prognostic factor for glioblastoma patient survival. SVZ pos glioblastoma had larger tumor size and a larger proportion of unmethylated tumors than SVZ neg glioblastoma. Further research is needed to establish whether the observed differences are solely explained by a different molecular profile of SVZ pos glioblastoma or by interaction of glioblastoma with the unique SVZ microenvironment.

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Section: Discussionmentioning

confidence: 90%

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival

et al. 2020

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“…Patients with GBM tumors located within the V‐SVZ exhibit shortened progression‐free survival that significantly diminishes overall survival . Treating these tumors results in the V‐SVZ being subjected to concurrent TMZ/XRT followed by adjuvant TMZ therapy.…”

Section: Discussionmentioning

confidence: 99%

Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular–Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation

et al. 2019

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The ventricular–subventricular zone (V‐SVZ) of the mammalian brain is a site of adult neurogenesis. Within the V‐SVZ reside type B neural stem cells (NSCs) and type A neuroblasts. The V‐SVZ is also a primary site for very aggressive glioblastoma (GBM). Standard‐of‐care therapy for GBM consists of safe maximum resection, concurrent temozolomide (TMZ), and X‐irradiation (XRT), followed by adjuvant TMZ therapy. The question of how this therapy impacts neurogenesis is not well understood and is of fundamental importance as normal tissue tolerance is a limiting factor. Here, we studied the effects of concurrent TMZ/XRT followed by adjuvant TMZ on type B stem cells and type A neuroblasts of the V‐SVZ in C57BL/6 mice. We found that chemoradiation induced an apoptotic response in type A neuroblasts, as marked by cleavage of caspase 3, but not in NSCs, and that A cells within the V‐SVZ were repopulated given sufficient recovery time. 53BP1 foci formation and resolution was used to assess the repair of DNA double‐strand breaks. Remarkably, the repair was the same in type B and type A cells. While Bax expression was the same for type A or B cells, antiapoptotic Bcl2 and Mcl1 expression was significantly greater in NSCs. Thus, the resistance of type B NSCs to TMZ/XRT appears to be due, in part, to high basal expression of antiapoptotic proteins compared with type A cells. This preclinical research, demonstrating that murine NSCs residing in the V‐SVZ are tolerant of standard chemoradiation therapy, supports a dose escalation strategy for treatment of GBM. stem cells 2019;37:1629–1639

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“…Tumor location greatly influences the prognosis of GBM patients. More than half of all patients with GBM have tumors that touch the lateral ventricle or even reach into an important brain neurogenic region known as the subventricular zone (SVZ) (10)(11)(12)(13)(14)(15). These patients have significantly worse outcomes in terms of median overall survival, time to progression, and recurrence (3,12).…”

Section: Introductionmentioning

confidence: 99%

Human Cerebrospinal Fluid Modulates Pathways Promoting Glioblastoma Malignancy

et al. 2021

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Glioblastoma (GBM) is the most common and devastating primary cancer of the central nervous system in adults. High grade gliomas are able to modify and respond to the brain microenvironment. When GBM tumors infiltrate the Subventricular zone (SVZ) they have a more aggressive clinical presentation than SVZ-distal tumors. We suggest that cerebrospinal fluid (CSF) contact contributes to enhance GBM malignant characteristics in these tumors. We evaluated the impact of human CSF on GBM, performing a transcriptome analysis on human primary GBM cells exposed to CSF to measure changes in gene expression profile and their clinical relevance on disease outcome. In addition we evaluated the proliferation and migration changes of CSF-exposed GBM cells in vitro and in vivo. CSF induced transcriptomic changes in pathways promoting cell malignancy, such as apoptosis, survival, cell motility, angiogenesis, inflammation, and glucose metabolism. A genetic signature extracted from the identified transcriptional changes in response to CSF proved to be predictive of GBM patient survival using the TCGA database. Furthermore, CSF induced an increase in viability, proliferation rate, and self-renewing capacity, as well as the migratory capabilities of GBM cells in vitro. In vivo, GBM cells co-injected with human CSF generated larger and more proliferative tumors compared to controls. Taken together, these results provide direct evidence that CSF is a key player in determining tumor growth and invasion through the activation of complex gene expression patterns characteristic of a malignant phenotype. These findings have diagnostic and therapeutic implications for GBM patients. The changes induced by CSF contact might play a role in the increased malignancy of SVZ-proximal GBM.

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Subventricular zone–associated glioblastoma: A call for translational research to guide clinical decision making

Cited by 6 publications

References 26 publications

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival

Subventricular zone contacting glioblastoma: tumor size, molecular biological factors and patient survival

Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular–Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation

Human Cerebrospinal Fluid Modulates Pathways Promoting Glioblastoma Malignancy

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