|
1
|
Rodríguez-Mendoza B, Figueroa-González A, Cano-Herrera G, Gutiérrez-Rosas LE, Romero-Torres CI, Victoria-García LO, González-Castillo P, Guerrero-Cázares H, Ibarra A. [Glioblastoma and its interaction with neurogenesis]. Rev Neurol 2024; 79:279-287. [PMID: 39540380 PMCID: PMC11605900 DOI: 10.33588/rn.7910.2024226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Indexed: 11/16/2024]
Abstract
Glioblastoma (GBM) is the most frequent and aggressive malignant primary tumor of the central nervous system in adults, with an incidence of 3.23 per 100,000 people. Despite the existence of various therapeutic approaches, the absence of a cure and the unfavorable prognosis persist for this neoplasm, with a median survival of approximately 8-15 months and a 5-year survival rate of 6.9%. In this review, we address the epidemiology, histopathology, molecular characteristics, and treatment of GBM. We highlight the relationship of GBM with the microenvironment in the lateral ventricle wall and the cerebrospinal fluid. The location of GBM in this region results in more aggressive tumors and shorter life expectancy for patients. Understanding the malignancy mechanisms that hinder remission, treatment, and positive prognosis opens the possibility of improving diagnostic and therapeutic interventions against GBM.
Collapse
Affiliation(s)
- Brenda Rodríguez-Mendoza
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
| | - Aura Figueroa-González
- Neurosurgery Department. Mayo Clinic Jacksonville. Jacksonville, Estados UnidosMayo Clinic JacksonvilleMayo Clinic JacksonvilleJacksonvilleEstados Unidos
| | - Gabriela Cano-Herrera
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
| | - Luis E. Gutiérrez-Rosas
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
| | - Carlos I. Romero-Torres
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
| | - Luis O. Victoria-García
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
| | - Paola González-Castillo
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
| | - Hugo Guerrero-Cázares
- Neurosurgery Department. Mayo Clinic Jacksonville. Jacksonville, Estados UnidosMayo Clinic JacksonvilleMayo Clinic JacksonvilleJacksonvilleEstados Unidos
| | - Antonio Ibarra
- Centro de Investigación en Ciencias de la Salud (CICSA). FCS. Universidad Anáhuac México Campus Norte. Huixquilucan. Ciudad de México, MéxicoUniversidad Anáhuac México Campus NorteUniversidad Anáhuac México Campus NorteCiudad de MéxicoMéxico
- Secretaría de la Defensa Nacional. Escuela Militar de Graduados en Sanidad. Ciudad de México, MéxicoEscuela Militar de Graduados en SanidadEscuela Militar de Graduados en SanidadCiudad de MéxicoMéxico
| |
Collapse
|
|
2
|
Ning W, Qian X, Dunmall LC, Liu F, Guo Y, Li S, Song D, Liu D, Ma L, Qu Y, Wang H, Gu C, Zhang M, Wang Y, Wang S, Zhang H. Non-secreting IL12 expressing oncolytic adenovirus Ad-TD-nsIL12 in recurrent high-grade glioma: a phase I trial. Nat Commun 2024; 15:9299. [PMID: 39516192 PMCID: PMC11549344 DOI: 10.1038/s41467-024-53041-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 09/30/2024] [Indexed: 11/16/2024] Open
Abstract
Malignant glioma is a highly fatal central nervous system malignancy with high recurrence rates. Oncolytic viruses offer potential treatment but need improvement in efficacy and safety. Here we describe a phase I, dose-escalating, single arm trial (ChiCTR2000032402) to study the safety of Ad-TD-nsIL12, an oncolytic adenovirus expressing non-secreting interleukin-12, in patients with recurrent high-grade glioma that connects with the ventricular system. Eight patients received intratumoral treatment via stereotaxis or an Ommaya reservoir, with doses ranging from 5 × 109 to 5 × 1010vp. The primary end point was to determine the maximal tolerated dose. Secondary endpoints included toxicity and anti-tumour ability. Minimal adverse events were observed at doses of 5 × 109 and 1 × 1010vp. Grade 3 seizure was observed in two patients from Cohort 3 (5 × 1010vp). Therefore, the maximum tolerated dose was determined to be 1 × 1010vp. Four patients developed hydrocephalus during follow-up. Among them, symptoms in two patients were relieved after placement of a ventriculo-peritoneal shunt, and the other two only showed ventriculomegaly on MRI scan without neurological deterioration. Complete response (according to Response Assessment in Neuro-Oncology Criteria) in one patient, a partial response in one patient and post-treatment infiltrations of CD4+ and CD8 + T cells into the tumour were documented during this trial. In conclusion, Ad-TD-nsIL12 has demonstrated safety and preliminary efficacy in patients with recurrent high-grade glioma.
Collapse
Affiliation(s)
- Weihai Ning
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Xiao Qian
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Louisa Chard Dunmall
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Funan Liu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yuduo Guo
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Shenglun Li
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Dixiang Song
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Deshan Liu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Lixin Ma
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Yanming Qu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Haoran Wang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chunyu Gu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Mingshan Zhang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Yaohe Wang
- Centre for Cancer Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, UK.
| | - Shengdian Wang
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
| | - Hongwei Zhang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
|
3
|
Norton ES, Whaley LA, Jones VK, Brooks MM, Russo MN, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann YW, Lam TT, Chaichana KL, Anastasiadis PZ, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific cross-talk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. SCIENCE ADVANCES 2024; 10:eadn1607. [PMID: 39110807 PMCID: PMC11305394 DOI: 10.1126/sciadv.adn1607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially because of subventricular zone contact. Despite this, cross-talk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. In addition, GBM brain tumor-initiating cells (BTICs) increase expression of cathepsin B (CTSB) upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal that both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Last, we show LV-proximal CTSB up-regulation in patients, showing the relevance of this cross-talk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM.
Collapse
Affiliation(s)
- Emily S. Norton
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
- Regenerative Sciences Training Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Lauren A. Whaley
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Vanessa K. Jones
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Biology, University of North Florida, Jacksonville, FL 32224, USA
| | - Mieu M. Brooks
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Marissa N. Russo
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Dmytro Morderer
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Erik Jessen
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
| | | | | | - Natanael Zarco
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Anna Carrano
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Wilfried Rossoll
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Yan W. Asmann
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA
| | - TuKiet T. Lam
- Keck MS and Proteomics Resource, Yale School of Medicine, New Haven, CT 06510, USA
- Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06510, USA
| | | | | | | | | |
Collapse
|
|
4
|
Norton ES, Whaley LA, Jones VK, Brooks MM, Russo MN, Morderer D, Jessen E, Schiapparelli P, Ramos-Fresnedo A, Zarco N, Carrano A, Rossoll W, Asmann YW, Lam TT, Chaichana KL, Anastasiadis PZ, Quiñones-Hinojosa A, Guerrero-Cázares H. Cell-specific crosstalk proteomics reveals cathepsin B signaling as a driver of glioblastoma malignancy near the subventricular zone. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.19.553966. [PMID: 37662251 PMCID: PMC10473635 DOI: 10.1101/2023.08.19.553966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Glioblastoma (GBM) is the most prevalent and aggressive malignant primary brain tumor. GBM proximal to the lateral ventricles (LVs) is more aggressive, potentially due to subventricular zone (SVZ) contact. Despite this, crosstalk between GBM and neural stem/progenitor cells (NSC/NPCs) is not well understood. Using cell-specific proteomics, we show that LV-proximal GBM prevents neuronal maturation of NSCs through induction of senescence. Additionally, GBM brain tumor initiating cells (BTICs) increase expression of CTSB upon interaction with NPCs. Lentiviral knockdown and recombinant protein experiments reveal both cell-intrinsic and soluble CTSB promote malignancy-associated phenotypes in BTICs. Soluble CTSB stalls neuronal maturation in NPCs while promoting senescence, providing a link between LV-tumor proximity and neurogenesis disruption. Finally, we show LV-proximal CTSB upregulation in patients, showing the relevance of this crosstalk in human GBM biology. These results demonstrate the value of proteomic analysis in tumor microenvironment research and provide direction for new therapeutic strategies in GBM. Highlights Periventricular GBM is more malignant and disrupts neurogenesis in a rodent model.Cell-specific proteomics elucidates tumor-promoting crosstalk between GBM and NPCs.NPCs induce upregulated CTSB expression in GBM, promoting tumor progression.GBM stalls neurogenesis and promotes NPC senescence via CTSB.
Collapse
|
|
5
|
Russo MN, Whaley LA, Norton ES, Zarco N, Guerrero-Cázares H. Extracellular vesicles in the glioblastoma microenvironment: A diagnostic and therapeutic perspective. Mol Aspects Med 2023; 91:101167. [PMID: 36577547 PMCID: PMC10073317 DOI: 10.1016/j.mam.2022.101167] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 11/29/2022] [Accepted: 12/12/2022] [Indexed: 12/28/2022]
Abstract
Glioblastoma (GBM), is the most malignant form of gliomas and the most common and lethal primary brain tumor in adults. Conventional cancer treatments have limited to no efficacy on GBM. GBM cells respond and adapt to the surrounding brain parenchyma known as tumor microenvironment (TME) to promote tumor preservation. Among specific TME, there are 3 of particular interest for GBM biology: the perivascular niche, the subventricular zone neurogenic niche, and the immune microenvironment. GBM cells and TME cells present a reciprocal feedback which results in tumor maintenance. One way that these cells can communicate is through extracellular vesicles. These vesicles include exosomes and microvesicles that have the ability to carry both cancerous and non-cancerous cargo, such as miRNA, RNA, proteins, lipids, and DNA. In this review we will discuss the booming topic that is extracellular vesicles, and how they have the novelty to be a diagnostic and targetable vehicle for GBM.
Collapse
Affiliation(s)
- Marissa N Russo
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA
| | - Lauren A Whaley
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Biology Graduate Program, University of North Florida, Jacksonville, FL, USA
| | - Emily S Norton
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA; Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Natanael Zarco
- Neurosurgery Department, Mayo Clinic, Jacksonville, FL, USA
| | | |
Collapse
|
|
6
|
Li S, Dong L, Pan Z, Yang G. Targeting the neural stem cells in subventricular zone for the treatment of glioblastoma: an update from preclinical evidence to clinical interventions. Stem Cell Res Ther 2023; 14:125. [PMID: 37170286 PMCID: PMC10173522 DOI: 10.1186/s13287-023-03325-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Glioblastoma is one of the most common and aggressive adult brain tumors. The conventional treatment strategy, surgery combined with chemoradiotherapy, did not change the fact that the recurrence rate was high and the survival rate was low. Over the years, accumulating evidence has shown that the subventricular zone has an important role in the recurrence and treatment resistance of glioblastoma. The human adult subventricular zone contains neural stem cells and glioma stem cells that are probably a part of reason for therapy resistance and recurrence of glioblastoma. MAIN BODY Over the years, both bench and bedside evidences strongly support the view that the presence of neural stem cells and glioma stem cells in the subventricular zone may be the crucial factor of recurrence of glioblastoma after conventional therapy. It emphasizes the necessity to explore new therapy strategies with the aim to target subventricular zone to eradicate neural stem cells or glioma stem cells. In this review, we summarize the recent preclinical and clinical advances in targeting neural stem cells in the subventricular zone for glioblastoma treatment, and clarify the prospects and challenges in clinical application. CONCLUSIONS Although there remain unresolved issues, current advances provide us with a lot of evidence that targeting the neural stem cells and glioma stem cells in subventricular zone may have the potential to solve the dilemma of glioblastoma recurrence and treatment resistance.
Collapse
Affiliation(s)
- Sijia Li
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, 130021 China
| | - Lihua Dong
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, 130021 China
| | - Zhenyu Pan
- Department of Radiation Oncology, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, 516000 China
| | - Guozi Yang
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun, 130021 China
- Department of Radiation Oncology, Huizhou Third People’s Hospital, Guangzhou Medical University, Huizhou, 516000 China
| |
Collapse
|
|
7
|
Liu L, Wang S, Dong X, Liu Y, Wei L, Kong L, Zhang Q, Zhang K. Trigone ventricular glioblastoma multiforme with trapped temporal horn: A case report. Front Oncol 2022; 12:995189. [PMID: 36176385 PMCID: PMC9513456 DOI: 10.3389/fonc.2022.995189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundIntraventricular glioblastoma multiforme (GBM) is extremely rare, especially in the trigone region. This report presents a case of trigone ventricular GBM with trapped temporal horn (TTH).Case presentationA 59-year-old woman was admitted to our department with a 1-month history of rapidly progressive headache, nausea, and weakness in the right lower extremity. Head non-contrast computed tomography and enhanced magnetic resonance imaging (MRI) revealed a trigone ventricular mass lesion with TTH and heterogeneous enhancement. The lesion was found 18 months ago as a small asymptomatic tumor mimicking ependymoma. This neoplasm was removed subtotally through the right parieto-occipital approach guided by neuroendoscopy. A ventriculoperitoneal shunt was subsequently performed to relieve TTH. The final pathological diagnosis was GBM. Unfortunately, 36 days after the first surgery, the patient died due to her family’s decision to refuse therapy.ConclusionThis rare case shows that GBM should be considered in the differential diagnosis of trigonal tumors. In this case, the tumor possibly originated from the neural stem cells in the subventricular zone. Patients with intraventricular GBM have a worse prognosis, and careful follow-up and early surgery for small intraventricular tumors are necessary, even for those with ependymoma-like radiological findings.
Collapse
Affiliation(s)
- Lei Liu
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Shaozhen Wang
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Xuetao Dong
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Yaodong Liu
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Liudong Wei
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Linghong Kong
- Department of Pathology, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Qingjun Zhang
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
| | - Kun Zhang
- Department of Neurosurgery, Chui Yang Liu Hospital Affiliated to Tsinghua University, Beijing, China
- *Correspondence: Kun Zhang,
| |
Collapse
|
|
8
|
Norton ES, Whaley LA, Ulloa-Navas MJ, García-Tárraga P, Meneses KM, Lara-Velazquez M, Zarco N, Carrano A, Quiñones-Hinojosa A, García-Verdugo JM, Guerrero-Cázares H. Glioblastoma disrupts the ependymal wall and extracellular matrix structures of the subventricular zone. Fluids Barriers CNS 2022; 19:58. [PMID: 35821139 PMCID: PMC9277938 DOI: 10.1186/s12987-022-00354-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/27/2022] [Indexed: 12/04/2022] Open
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. Supplementary Information The online version contains supplementary material available at 10.1186/s12987-022-00354-8.
Collapse
Affiliation(s)
- Emily S Norton
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.,Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA.,Regenerative Sciences Training Program, Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Lauren A Whaley
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.,Department of Biology, University of North Florida, Jacksonville, FL, USA
| | - María José Ulloa-Navas
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, Paterna, Spain.,Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - Patricia García-Tárraga
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, Paterna, Spain
| | - Kayleah M Meneses
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.,Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL, USA
| | | | - Natanael Zarco
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | - Anna Carrano
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA
| | | | - José Manuel García-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, CIBERNED, Paterna, Spain
| | - Hugo Guerrero-Cázares
- Department of Neurosurgery, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
| |
Collapse
|
|
9
|
Sowers ML, Sowers LC. Glioblastoma and Methionine Addiction. Int J Mol Sci 2022; 23:7156. [PMID: 35806160 PMCID: PMC9266821 DOI: 10.3390/ijms23137156] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/21/2022] [Accepted: 06/24/2022] [Indexed: 02/01/2023] Open
Abstract
Glioblastoma is a fatal brain tumor with a bleak prognosis. The use of chemotherapy, primarily the alkylating agent temozolomide, coupled with radiation and surgical resection, has provided some benefit. Despite this multipronged approach, average patient survival rarely extends beyond 18 months. Challenges to glioblastoma treatment include the identification of functional pharmacologic targets as well as identifying drugs that can cross the blood-brain barrier. To address these challenges, current research efforts are examining metabolic differences between normal and tumor cells that could be targeted. Among the metabolic differences examined to date, the apparent addiction to exogenous methionine by glioblastoma tumors is a critical factor that is not well understood and may serve as an effective therapeutic target. Others have proposed this property could be exploited by methionine dietary restriction or other approaches to reduce methionine availability. However, methionine links the tumor microenvironment with cell metabolism, epigenetic regulation, and even mitosis. Therefore methionine depletion could result in complex and potentially undesirable responses, such as aneuploidy and the aberrant expression of genes that drive tumor progression. If methionine manipulation is to be a therapeutic strategy for glioblastoma patients, it is essential that we enhance our understanding of the role of methionine in the tumor microenvironment.
Collapse
Affiliation(s)
- Mark L. Sowers
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA;
- MD-PhD Combined Degree Program, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
| | - Lawrence C. Sowers
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA;
- Department of Internal Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
| |
Collapse
|
|
10
|
Ramos-Fresnedo A, Pullen MW, Perez-Vega C, Domingo RA, Akinduro OO, Almeida JP, Suarez-Meade P, Marenco-Hillembrand L, Jentoft ME, Bendok BR, Trifiletti DM, Chaichana KL, Porter AB, Quiñones-Hinojosa A, Burns TC, Kizilbash SH, Middlebrooks EH, Sherman WJ. The survival outcomes of molecular glioblastoma IDH-wildtype: a multicenter study. J Neurooncol 2022; 157:177-185. [PMID: 35175545 DOI: 10.1007/s11060-022-03960-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/01/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE Histological diagnosis of glioblastoma (GBM) was determined by the presence of necrosis or microvascular proliferation (histGBM). The 2021 WHO classification now considers IDH-wildtype diffuse astrocytic tumors without the histological features of glioblastoma (that would have otherwise been classified as grade 2 or 3) as molecular GBM (molGBM, WHO grade 4) if they harbor any of the following molecular abnormalities: TERT promoter mutation, EGFR amplification, or chromosomal + 7/- 10 copy changes. The objective of this study was to explore and compare the survival outcomes between histGBM and molGBM. METHODS Medical records for patients diagnosed with GBM at the three tertiary care academic centers of our institution from November 2017 to October 2021. Only patients who underwent adjuvant chemoradiation were included. Patients without molecular feature testing or with an IDH mutation were excluded. Univariable and multivariable analyses were performed to evaluate progression-free (PFS) and overall- survival (OS). RESULTS 708 consecutive patients were included; 643 with histGBM and 65 with molGBM. Median PFS was 8 months (histGBM) and 13 months (molGBM) (p = 0.0237) and median OS was 21 months (histGBM) versus 26 months (molGBM) (p = 0.435). Multivariable analysis on the molGBM sub-group showed a worse PFS if there was contrast enhancement on MRI (HR 6.224 [CI 95% 2.187-17.714], p < 0.001) and a superior PFS on patients with MGMT methylation (HR 0.026 [CI 95% 0.065-0.655], p = 0.007). CONCLUSIONS molGBM has a similar OS but significantly longer PFS when compared to histGBM. The presence of contrast enhancement and MGMT methylation seem to affect the clinical behavior of this subset of tumors.
Collapse
Affiliation(s)
| | | | | | | | | | - Joao P Almeida
- Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA
| | | | | | - Mark E Jentoft
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL, USA
| | | | | | | | - Alyx B Porter
- Department of Neurology, Mayo Clinic, Phoenix, AZ, USA
| | | | | | | | | | - Wendy J Sherman
- Division Chair, Neuro-Oncology, Department of Neurology, Mayo Clinic, 4500 San Pablo Rd. S, Jacksonville, FL, 32224, USA.
| |
Collapse
|