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Firuzpour F, Saleki K, Aram C, Rezaei N. Nanocarriers in glioblastoma treatment: a neuroimmunological perspective. Rev Neurosci 2024:revneuro-2024-0097. [PMID: 39733347 DOI: 10.1515/revneuro-2024-0097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 12/08/2024] [Indexed: 12/31/2024]
Abstract
Glioblastoma multiforme (GBM) is the most fatal brain tumor with a poor prognosis with current treatments, mainly because of intrinsic resistance processes. GBM is also referred to as grade 4 astrocytoma, that makes up about 15.4 % of brain cancers globally as well as 60-75 % of astrocytoma. The most prevalent therapeutic choices for GBM comprise surgery in combination with radiotherapy and chemotherapy, providing patients with an average survival of 6-14 months. Nanocarriers provide various benefits such as enhanced drug solubility, biocompatibility, targeted activity, as well as minimized side effects. In addition, GBM treatment comes with several challenges such as the presence of the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), overexpressed efflux pumps, infiltration, invasion, drug resistance, as well as immune escape due to tumor microenvironment (TME) and cancer stem cells (CSC). Recent research has focused on nanocarriers due to their ability to self-assemble, improve bioavailability, provide controlled release, and penetrate the BBB. These nano-based components could potentially enhance drug accumulation in brain tumor tissues and reduce systemic toxicity, making them a compelling solution for GBM therapy. This review captures the complexities associated with multi-functional nano drug delivery systems (NDDS) in crossing the blood-brain barrier (BBB) and targeting cancer cells. In addition, it presents a succinct overview of various types of targeted multi-functional nano drug delivery system (NDDS) which has exhibited promising value for improving drug delivery to the brain.
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Affiliation(s)
- Faezeh Firuzpour
- USERN Office, Babol University of Medical Sciences, 47176-41367, Babol, Iran
- Student Research Committee, Babol University of Medical Sciences, 47176-41367, Babol, Iran
| | - Kiarash Saleki
- USERN Office, Babol University of Medical Sciences, 47176-41367, Babol, Iran
- Student Research Committee, Babol University of Medical Sciences, 47176-41367, Babol, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
| | - Cena Aram
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, 15719-14911, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Department of Immunology, School of Medicine, 48439 Tehran University of Medical Sciences , Tehran, 1416634793, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, 1416634793, Iran
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Kim KS, Habashy K, Gould A, Zhao J, Najem H, Amidei C, Saganty R, Arrieta VA, Dmello C, Chen L, Zhang DY, Castro B, Billingham L, Levey D, Huber O, Marques M, Savitsky DA, Morin BM, Muzzio M, Canney M, Horbinski C, Zhang P, Miska J, Padney S, Zhang B, Rabadan R, Phillips JJ, Butowski N, Heimberger AB, Hu J, Stupp R, Chand D, Lee-Chang C, Sonabend AM. Fc-enhanced anti-CTLA-4, anti-PD-1, doxorubicin, and ultrasound-mediated blood-brain barrier opening: A novel combinatorial immunotherapy regimen for gliomas. Neuro Oncol 2024; 26:2044-2060. [PMID: 39028616 PMCID: PMC11534315 DOI: 10.1093/neuonc/noae135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Indexed: 07/21/2024] Open
Abstract
BACKGROUND Glioblastoma is a highly aggressive brain cancer that is resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in "cold" and immunotherapy-refractory cancers. METHODS We evaluated the efficacy and immune microenvironment phenotype of a mouse analogue of FcE-aCTLA-4 in treatment-refractory preclinical models of glioblastoma, both as a monotherapy and in combination with doxorubicin delivered via low-intensity pulsed ultrasound and microbubbles (LIPU/MB). Additionally, we studied 4 glioblastoma patients treated with doxorubicin, anti-PD-1 with concomitant LIPU/MB to investigate the novel effect of doxorubicin modulating FcγR expressions in tumor-associated macrophages/microglia (TAMs). RESULTS FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed in TAMs in human glioblastoma, most robustly at diagnosis. Notably, FcE-aCTLA-4-mediated selective depletion of intratumoral regulatory T cells (Tregs) via TAM-mediated phagocytosis, while sparing peripheral Tregs. Doxorubicin, a chemotherapeutic drug with immunomodulatory functions, was found to upregulate FcγRIIIA on TAMs in glioblastoma patients who received doxorubicin and anti-PD-1 with concomitant LIPU/MB. In murine models of immunotherapy-resistant gliomas, a combinatorial regimen of FcE-aCTLA-4, anti-PD-1, and doxorubicin with LIPU/MB, achieved a 90% cure rate, that was associated robust infiltration of activated CD8+ T cells and establishment of immunological memory as evidenced by rejection upon tumor rechallenge. CONCLUSIONS Our findings demonstrate that FcE-aCTLA-4 promotes robust immunomodulatory and anti-tumor effects in murine gliomas and is significantly enhanced when combined with anti-PD-1, doxorubicin, and LIPU/MB. We are currently investigating this combinatory strategy in a clinical trial (clinicaltrials.gov NCT05864534).
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Affiliation(s)
- Kwang-Soo Kim
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Karl Habashy
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Andrew Gould
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Junfei Zhao
- Department of Biomedical Informatics, Columbia University, New York, New York, USA
- Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, New York, USA
- Department of Systems Biology, Columbia University, New York, New York, USA
| | - Hinda Najem
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Christina Amidei
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Ruth Saganty
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Víctor A Arrieta
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Crismita Dmello
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Li Chen
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Daniel Y Zhang
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Brandyn Castro
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Leah Billingham
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | | | | | | | | | | | - Miguel Muzzio
- Life Science Group, IIT Research Institute (IITRI), Chicago, Illinois, USA
| | | | - Craig Horbinski
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Peng Zhang
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jason Miska
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Surya Padney
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Bin Zhang
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Raul Rabadan
- Department of Biomedical Informatics, Columbia University, New York, New York, USA
- Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, New York, USA
- Department of Systems Biology, Columbia University, New York, New York, USA
| | - Joanna J Phillips
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - Nicholas Butowski
- Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
| | - Amy B Heimberger
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Jian Hu
- Division of Basic Science Research, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Roger Stupp
- Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Dhan Chand
- Agenus Inc., Lexington, Massachusetts, USA
| | - Catalina Lee-Chang
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
| | - Adam M Sonabend
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
- Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA
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Sarantopoulos A, Ene C, Aquilanti E. Therapeutic approaches to modulate the immune microenvironment in gliomas. NPJ Precis Oncol 2024; 8:241. [PMID: 39443641 PMCID: PMC11500177 DOI: 10.1038/s41698-024-00717-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/18/2024] [Indexed: 10/25/2024] Open
Abstract
Immunomodulatory therapies, including immune checkpoint inhibitors, have drastically changed outcomes for certain cancer types over the last decade. Gliomas are among the cancers that have seem limited benefit from these agents, with most trials yielding negative results. The unique composition of the glioma immune microenvironment is among the culprits for this lack of efficacy. In recent years, several efforts have been made to improve understanding of the glioma immune microenvironment, aiming to pave the way for novel therapeutic interventions. In this review, we discuss some of the main components of the glioma immune microenvironment, including macrophages, myeloid-derived suppressor cells, neutrophils and microglial cells, as well as lymphocytes. We then provide a comprehensive overview of novel immunomodulatory agents that are currently in clinical development, namely oncolytic viruses, vaccines, cell-based therapies such as CAR-T cells and CAR-NK cells as well as antibodies and peptides.
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Affiliation(s)
| | - Chibawanye Ene
- Department of Neurosurgery, The University of Texas M D Anderson Cancer Center, Houston, TX, USA
| | - Elisa Aquilanti
- Center for Neuro-Oncology, Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
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Zhou J, Guo L, Wang Y, Li L, Guo Y, Duan L, Jiao M, Xi P, Wang P. Development and validation of a risk prognostic model based on the H. pylori infection phenotype for stomach adenocarcinoma. Heliyon 2024; 10:e36882. [PMID: 39281596 PMCID: PMC11401198 DOI: 10.1016/j.heliyon.2024.e36882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/23/2024] [Accepted: 08/23/2024] [Indexed: 09/18/2024] Open
Abstract
Background Stomach adenocarcinoma (STAD) is one of the most common malignancies. Infection of helicobacter pylori (H. pylori) is a major risk factor that leads to the development of STAD. This study constructed a risk model based on the H. pylori-related macrophages for predicting STAD prognosis. Methods The single-cell RNA sequencing (scRNA-seq) dataset and the clinic information and RNA-seq datasets of STAD patients were collected for establishing a prognostic model and for validation. The "Seurat" and "harmony" packages were used to process the scRNA-seq data. Key gene modules were sectioned using the "limma" package and the "WGCNA" package. Kaplan-Meier (KM) and Receiver Operating Characteristic Curve (ROC) analyses were performed with "survminer" package. The "GSVA" package was employed for single sample gene set enrichment analysis (ssGSEA). Cell migration and invasion were measured by carrying out wound healing and trans-well assays. Results A total of 17397 were screened and classified into 8 cell type clusters, among which the macrophage cluster was closely associated with the H. pylori infection. Macrophages were further categorized into four subtypes (including C1, C2, C3, and C4), and highly variable genes of macrophage subtype C4 could serve as an indicator of the prognosis of STAD. Subsequently, we developed a RiskScore model based on six H. pylori -associated genes (TNFRSF1B, CTLA4, ABCA1, IKBIP, AKAP5, and NPC2) and observed that the high-risk patients exhibited poor prognosis, higher suppressive immune infiltration, and were closely associated with cancer activation-related pathways. Furthermore, a nomogram combining the RiskScore was developed to accurately predict the survival of STAD patients. AB CA 1 in the RiskScore model significantly affected the migration and invasion of tumor cells. Conclusion The gene expression profile served as an indicator of the survival for patients with STAD and addressed the clinical significance of using H. pylori-associated genes to treat STAD. The current findings provided novel understandings for the clinical evaluation and management of STAD.
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Affiliation(s)
- Jing Zhou
- Department of Oncology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Li Guo
- Department of Geriatrics, South District, 986th Hospital of the People's Liberation Army Air Force, Xi'an, 710054, China
| | - Yuzhen Wang
- Department of Oncology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Lina Li
- Department of Oncology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Yahuan Guo
- Department of Oncology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Lian Duan
- Department of Oncology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Mi Jiao
- Department of Oncology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Pan Xi
- Department of Radiotherapy, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
| | - Pei Wang
- Department of Anesthesiology, Shaanxi Province Tumor Hospital, Xi'an, 710061, China
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5
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Vishnoi M, Dereli Z, Yin Z, Kong EK, Kinali M, Thapa K, Babur O, Yun K, Abdelfattah N, Li X, Bozorgui B, Farach-Carson MC, Rostomily RC, Korkut A. A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches. RESEARCH SQUARE 2024:rs.3.rs-4541464. [PMID: 38947019 PMCID: PMC11213219 DOI: 10.21203/rs.3.rs-4541464/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Background Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Methods Here, through computational genomics and proteomics approaches, we analyzed the functional and clinical relevance of CMP expression in GBM at bulk, single cell, and spatial anatomical resolution. Results We identified genes encoding CMPs whose expression levels categorize GBM tumors into CMP expression-high (M-H) and CMP expression-low (M-L) groups. CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells, and immune checkpoint gene expression. Anatomical and single-cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene CMP expression signature, termed Matrisome 17 (M17) signature that further refines the prognostic value of CMP genes. The M17 signature is a significantly stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, potentially predicts responses to PD1 blockade. Conclusion The matrisome gene expression signature provides a robust stratification of GBM patients by survival and potential biomarkers of functionally relevant GBM niches that can mediate mesenchymal-immune cross talk. Patient stratification based on matrisome profiles can contribute to selection and optimization of treatment strategies.
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Affiliation(s)
- Monika Vishnoi
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurosurgery, Weill Cornell Medical School, New York NY, 10065
| | - Zeynep Dereli
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zheng Yin
- Department of Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center, Houston, TX, 77030 USA
| | - Elisabeth K. Kong
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Statistics, Rice University, Houston, TX, 77030, USA
| | - Meric Kinali
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Kisan Thapa
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Ozgun Babur
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Kyuson Yun
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurology, Weill Cornell Medical School, New York NY, 10065
| | - Nourhan Abdelfattah
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurology, Weill Cornell Medical School, New York NY, 10065
| | - Xubin Li
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Behnaz Bozorgui
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mary C. Farach-Carson
- Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA
- Departments of BioSciences and Bioengineering, Rice University, Houston, TX, 77005, USA
| | - Robert C. Rostomily
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurosurgery, University of Washington School of Medicine, Seattle WA, 98195
- Department of Neurosurgery, Weill Cornell Medical School, New York NY, 10065
| | - Anil Korkut
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
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Hashemi M, Mousavian Roshanzamir S, Orouei S, Daneii P, Raesi R, Zokaee H, Bikarannejad P, Salmani K, Khorrami R, Deldar Abad Paskeh M, Salimimoghadam S, Rashidi M, Hushmandi K, Taheriazam A, Entezari M. Shedding light on function of long non-coding RNAs (lncRNAs) in glioblastoma. Noncoding RNA Res 2024; 9:508-522. [PMID: 38511060 PMCID: PMC10950594 DOI: 10.1016/j.ncrna.2024.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/29/2024] [Accepted: 02/04/2024] [Indexed: 03/22/2024] Open
Abstract
The brain tumors and especially glioblastoma, are affecting life of many people worldwide and due to their high mortality and morbidity, their treatment is of importance and has gained attention in recent years. The abnormal expression of genes is commonly observed in GBM and long non-coding RNAs (lncRNAs) have demonstrated dysregulation in this tumor. LncRNAs have length more than 200 nucleotides and they have been located in cytoplasm and nucleus. The current review focuses on the role of lncRNAs in GBM. There two types of lncRNAs in GBM including tumor-promoting and tumor-suppressor lncRNAs and overexpression of oncogenic lncRNAs increases progression of GBM. LncRNAs can regulate proliferation, cell cycle arrest and metastasis of GBM cells. Wnt, STAT3 and EZH2 are among the molecular pathways affected by lncRNAs in GBM and for regulating metastasis of GBM cells, these RNA molecules mainly affect EMT mechanism. LncRNAs are involved in drug resistance and can induce resistance of GBM cells to temozolomide chemotherapy. Furthermore, lncRNAs stimulate radio-resistance in GBM cells. LncRNAs increase PD-1 expression to mediate immune evasion. LncRNAs can be considered as diagnostic and prognostic tools in GBM and researchers have developed signature from lncRNAs in GBM.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sophie Mousavian Roshanzamir
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sima Orouei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Pouria Daneii
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Rasoul Raesi
- Department of Nursing, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Haleh Zokaee
- Department of Oral and Maxillofacial Medicine, Dental Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Pooria Bikarannejad
- Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Kiana Salmani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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7
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Montes-Escobar K, de la Hoz-M J, Castillo-Cordova P, Duran-Ospina JP, Bravo-Saltos RK, Lapo-Talledo GJ, Siteneski A. Glioblastoma: a comprehensive approach combining bibliometric analysis, Latent Dirichlet Allocation, and HJ-Biplot : Glioblastoma insights and trends: a 49-year bibliometric analysis. Neurosurg Rev 2024; 47:209. [PMID: 38724684 DOI: 10.1007/s10143-024-02440-x] [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: 11/24/2023] [Revised: 03/28/2024] [Accepted: 04/27/2024] [Indexed: 06/26/2024]
Abstract
Glioblastoma is a common and aggressive malignant central nervous system tumor in adults. This study aims to evaluate and analyze the scientific results, collaboration countries, main research topics, and topics over time reported about glioblastoma. A bibliometric analysis of glioblastoma publications was performed mainly using R and Multbiplot software for author, journal, and resume. Associated statistic methods Latent Dirichlet Allocation (LDA) and HJ-Biplot. Inclusion criteria were research articles from the PubMed database published in English between 1973 and December 2022. A total of 64,823 documents with an annual growth rate of 8.27% indicates a consistent increase in research output over time. The results for the number of citations and significant publications showed Cancer Res, J Neuro-Oncol, and Neuro-Oncology are the most influential journals in the field of glioblastoma. The countries that concentrated research were the tumor United States, China, Germany, and Italy. Finally, there has been a marked growth in studies on prognosis and patient survival, therapies, and treatments for glioblastoma. These findings reinforce the need for increased global resources to address glioblastoma, particularly in underdeveloped countries. Glioblastoma research's exponential growth reflects sustained interest in early diagnosis and patient survival.
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Affiliation(s)
- Karime Montes-Escobar
- Departamento de Matemáticas y Estadística, Faculta de Ciencias Básicas, Universidad Técnica de Manabí, Portoviejo, 130105, Ecuador
- Statistics Department, University of Salamanca, Salamanca, 37007, Spain
| | - Javier de la Hoz-M
- Statistics Department, University of Salamanca, Salamanca, 37007, Spain
- Universidad del Magdalena, Santa Marta, 470004, Colombia
| | - Paul Castillo-Cordova
- SOLCA Nucleus Loja, Loja, 110105, Ecuador
- Carrera de Medicina, Facultad de Ciencias de la Salud,, Universidad Técnica Particular de Loja, Loja, 1101608 , Ecuador
| | | | - Rosalba Karen Bravo-Saltos
- Departamento de Matemáticas y Estadística, Faculta de Ciencias Básicas, Universidad Técnica de Manabí, Portoviejo, 130105, Ecuador
| | - German Josuet Lapo-Talledo
- School of Medicine, Faculty of Health Sciences, Universidad Técnica de Manabí, Portoviejo, 130105, Ecuador
| | - Aline Siteneski
- School of Medicine, Faculty of Health Sciences, Universidad Técnica de Manabí, Portoviejo, 130105, Ecuador.
- Research Institute, Faculty of Health Sciences, Medicine Career, Universidad Técnica de Manabí, Portoviejo, 130105, Ecuador.
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8
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Jin T, Park KS, Nam SE, Lim SH, Kim JH, Noh WC, Yoo YB, Park WS, Yun IJ. CTLA4 expression profiles and their association with clinical outcomes of breast cancer: a systemic review. Ann Surg Treat Res 2024; 106:263-273. [PMID: 38725802 PMCID: PMC11076949 DOI: 10.4174/astr.2024.106.5.263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/16/2024] [Accepted: 03/03/2024] [Indexed: 05/12/2024] Open
Abstract
Purpose The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is involved in the progression of various cancers, but its biological roles in breast cancer (BRCA) remain unclear. Therefore, we performed a systematic multiomic analysis to expound on the prognostic value and underlying mechanism of CTLA4 in BRCA. Methods We assessed the effect of CTLA4 expression on BRCA using a variety of bioinformatics platforms, including Oncomine, GEPIA, UALCAN, PrognoScan database, Kaplan-Meier plotter, and R2: Kaplan-Meier scanner. Results CTLA4 was highly expressed in BRCA tumor tissue compared to normal tissue (P < 0.01). The CTLA4 messenger RNA levels in BRCA based on BRCA subtypes of Luminal, human epidermal growth factor receptor 2, and triple-negative BRCA were considerably higher than in normal tissues (P < 0.001). However, the overexpression of CTLA4 was associated with a better prognosis in BRCA (P < 0.001) and was correlated with clinicopathological characteristics including age, T stage, estrogen receptors, progesterone receptors, and prediction analysis of microarray 50 (P < 0.01). The infiltration of multiple immune cells was associated with increased CTLA4 expression in BRCA (P < 0.001). CTLA4 was highly enriched in antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. Conclusion This study provides suggestive evidence of the prognostic role of CTLA4 in BRCA, which may be a therapeutic target for BRCA. Furthermore, CTLA4 may influence BRCA prognosis through antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. These findings help us understand how CTLA4 plays a role in BRCA and set the stage for more research.
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Affiliation(s)
- TongYi Jin
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
| | - Kyoung Sik Park
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
| | - Sang Eun Nam
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
| | - Seung Hwan Lim
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
| | - Jong Hyun Kim
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
| | - Woo Chul Noh
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
| | - Young Bum Yoo
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
| | - Won Seo Park
- Department of Surgery, Kyung Hee University School of Medicine, Seoul, Korea
| | - Ik Jin Yun
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Department of Surgery, Konkuk University Medical Center, Seoul, Korea
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9
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Montoya M, Gallus M, Phyu S, Haegelin J, de Groot J, Okada H. A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives. Cells 2024; 13:726. [PMID: 38727262 PMCID: PMC11083543 DOI: 10.3390/cells13090726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/20/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and a nearly 100% mortality rate under standard therapy that consists of surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success of chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical and clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding the effectiveness of CAR-T-cell therapy for GBM, encompassing the cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local and systemic immunosuppression, and the immune privilege inherent to the central nervous system (CNS) parenchyma. Additionally, we deliberate on the progress made in developing next-generation CAR-T cells and novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks in GBM CAR-T-cell therapy.
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Affiliation(s)
- Megan Montoya
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Marco Gallus
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Su Phyu
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Jeffrey Haegelin
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - John de Groot
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Hideho Okada
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
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Zhuang Y, Chen J, Mai Z, Huang W, Zhong W. Signature Construction and Disulfidptosis-Related Molecular Cluster Identification for Better Prediction of Prognosis in Glioma. J Mol Neurosci 2024; 74:38. [PMID: 38573391 DOI: 10.1007/s12031-024-02216-4] [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: 11/12/2023] [Accepted: 03/24/2024] [Indexed: 04/05/2024]
Abstract
Disulfidptosis is a newly discovered form of regulatory cell death. However, the identification of disulfidptosis-related molecular subtypes and potential biomarkers in gliomas and their prognostic predictive potential need to be further elucidated. RNA sequencing profiles and the relevant clinical data were obtained from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Disulfidptosis-related clusters were identified by unsupervised clustering analysis. Immune cell infiltration analysis and drug sensitivity analysis were used to explore the differences between clusters. Gene set enrichment analysis (GSEA) of differential genes between clusters was performed to explore the potential biological functions and signaling. A disulfidptosis-related scoring system (DRSS) was constructed based on a combined COX and LASSO analysis. Mendelian randomization (MR) analyses were used to further explore the causal relationship between levels of genes in DRSS and an increased risk of glioma. A prognosis nomogram was constructed based on the DRSS and 3 clinical features (age, WHO stage, and IDH status). The accuracy and stability of the prognosis nomogram were also validated in different cohorts. We identified two clusters that exhibited different prognoses, drug sensitivity profiles, and tumor microenvironment infiltration profiles. The overall survival (OS) of Cluster2 was significantly better than Cluster1. Cluster1 had an overall greater infiltration of immune cells compared to Cluster2. However, the Monocytes, activated B cells had higher infiltration abundance in Cluster2. GSEA results showed significant enrichment of immune-related biological processes in Cluster1, while Cluster2 was more enriched for functions related to neurotransmission and regulation. PER3, RAB34, NKX3-2, GPX7, FRA10AC1, and TGIF1 were finally included to construct DRSS. DRSS was independently related to prognosis. There was a significant difference in overall survival between the low-risk score group and the high-risk score group. Among six genes in DRSS, GPX7 levels were demonstrated to have a causal relationship with an increased risk of glioma. GPX7 may become a more promising biomarker for gliomas. The prognosis nomogram constructed based on the DRSS and three clinical features has considerable potential for predicting the prognosis of patients with glioma. Free online software for implementing this nomogram was established: https://yekun-zhuang.shinyapps.io/DynNomapp/ . Our study established a novel glioma classification based on the disulfidptosis-related molecular subtypes. We constructed the DRSS and the prognosis nomogram to accurately stratify the prognosis of glioma patients. GPX7 was identified as a more promising biomarker for glioma. We provide important insights into the treatment and prognosis of gliomas.
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Affiliation(s)
- Yekun Zhuang
- The Sixth Clinical Medical School, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.
| | - Jiewen Chen
- The Sixth Clinical Medical School, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Zhuohao Mai
- The Sixth Clinical Medical School, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Wanting Huang
- The Sixth Clinical Medical School, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Wenyu Zhong
- The Sixth Clinical Medical School, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
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Yu L, Hu X, Zhu H. Predictive value of procollagen c-protease enhancer protein on the prognosis of glioma patients. Heliyon 2024; 10:e28089. [PMID: 38533063 PMCID: PMC10963382 DOI: 10.1016/j.heliyon.2024.e28089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 03/09/2024] [Accepted: 03/12/2024] [Indexed: 03/28/2024] Open
Abstract
Procollagen c-protease enhancer protein (PCOLCE) performs an essential action in improving the recreation of procollagen c-protease and promoting the reconstruction of extracellular matrix. High PCOLCE expression was associated with a negative prognosis of stomach cancer, ovarian cancer, and osteosarcoma. The goal of this work is to investigate the function of PCOLCE in glioma. Multiple bioinformatics techniques have been employed to investigate the roles of PCOLCE in glioma, consisting of the correlation between PCOLCE and prognosis, immune checkpoints, immune cell infiltrates, and tumor microenvironment (TME). The gene ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to assess the potential function of PCOLCE in glioma. PCOLCE was found to be increased in glioma. We revealed that PCOLCE was a potential prognostic factor and related to tumor grade. Up-regulated PCOLCE was related to poor prognosis in lower-grade glioma (LGG), glioblastoma multiforme (GBM), and recurrent glioma. PCOLCE was correlated with immune cell infiltration, particularly B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in LGG, and DCs infiltration in GBM. PCOLCE was co-expressed with many genes related to the immune and the immune checkpoint. In addition, glioma patients with low expression of PCOLCE had a higher response to the immunological checkpoint blockade (ICB). Additionally, PCOLCE may exert its roles via several immune-related biological processes or pathways, such as leukocyte migration, activation of T cells, adaptive immune response, neutrophil-mediated immunity, NF-κB, and TNF signaling pathways. In conclusion, PCOLCE may be a new immune-related gene and regulate tumor development through immunological pathways.
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Affiliation(s)
- Luli Yu
- Department of Neurosurgery, Shangrao People's Hospital, Shangrao, 334000, Jiangxi Province, China
| | - Xinyao Hu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China
| | - Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China
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12
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Luo S, Liu Z, Chang H, Cheng X, Qian R, Gao Y, Hou C. Potential value of expression of receptor accessory protein 4 for evaluating the prognosis of lower-grade glioma patients. Aging (Albany NY) 2024; 16:6188-6211. [PMID: 38552216 PMCID: PMC11042925 DOI: 10.18632/aging.205695] [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: 12/16/2023] [Accepted: 12/18/2023] [Indexed: 04/23/2024]
Abstract
BACKGROUND REEP4 is involved in the regulation of the biological process of mitosis. Lower grade glioma (LGG), as a malignant tumor, is accompanied by abnormalities in mitosis, but there have been no reports of REEP4 so far. METHODS We collected transcriptome data, DNA methylation data and the clinical characteristics of thousands of patients with LGG. Various big data analysis methods and molecular biology experiments were employed to reveal the impact of REEP4 on the pathological process of LGG. RESULTS It was found that the expression of REEP4 was significantly elevated and negatively regulated by its methylation site. Therefore, both the high expression of REEP4 and low methylation state of cg16311504 showed that the patients are correlated with lower patient survival rate. In addition, high REEP4 expression participates in the regulation of various cancer-related cellular signaling pathways, such as the cell cycle, MAPK signaling pathway, NOD-like receptor signaling pathway, etc. More importantly, the level of immune cell infiltration significantly increased in the high expression group of REEP4 in the LGG tumor microenvironment and REEP4 has a high positive correlation with PD-L1 and other immune checkpoints. CONCLUSIONS In brief, this study is the first to introduce REEP4 in malignant tumors, which can be used as an independent risk factor that participates in the malignant process of LGG. More importantly, REEP4 has the potential to become a new star in the field of anti-tumor treatment.
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Affiliation(s)
- Shuping Luo
- Department of Colorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China
| | - Zhendong Liu
- Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou 450003, Henan, China
| | - Haigang Chang
- Department of Neurosurgery, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
| | - Xingbo Cheng
- Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou 450003, Henan, China
| | - Rongjun Qian
- Department of Neurosurgery, Henan Provincial People’s Hospital, People’s Hospital of Henan University, People’s Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China
| | - Yanzheng Gao
- Department of Surgery of Spine and Spinal Cord, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou 450003, Henan, China
| | - Chaofeng Hou
- Department of Colorectal Surgery, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China
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Regmi M, Wang Y, Liu W, Dai Y, Liu S, Ma K, Lin G, Yang J, Liu H, Wu J, Yang C. From glioma gloom to immune bloom: unveiling novel immunotherapeutic paradigms-a review. J Exp Clin Cancer Res 2024; 43:47. [PMID: 38342925 PMCID: PMC10860318 DOI: 10.1186/s13046-024-02973-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/04/2024] [Indexed: 02/13/2024] Open
Abstract
In tumor therapeutics, the transition from conventional cytotoxic drugs to targeted molecular therapies, such as those targeting receptor tyrosine kinases, has been pivotal. Despite this progress, the clinical outcomes have remained modest, with glioblastoma patients' median survival stagnating at less than 15 months. This underscores the urgent need for more specialized treatment strategies. Our review delves into the progression toward immunomodulation in glioma treatment. We dissect critical discoveries in immunotherapy, such as spotlighting the instrumental role of tumor-associated macrophages, which account for approximately half of the immune cells in the glioma microenvironment, and myeloid-derived suppressor cells. The complex interplay between tumor cells and the immune microenvironment has been explored, revealing novel therapeutic targets. The uniqueness of our review is its exhaustive approach, synthesizing current research to elucidate the intricate roles of various molecules and receptors within the glioma microenvironment. This comprehensive synthesis not only maps the current landscape but also provides a blueprint for refining immunotherapy for glioma, signifying a paradigm shift toward leveraging immune mechanisms for improved patient prognosis.
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Affiliation(s)
- Moksada Regmi
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
- Peking University Health Science Center, Beijing, 100191, China
- Henan Academy of Innovations in Medical Science (AIMS), Zhengzhou, 450003, China
| | - Yingjie Wang
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
| | - Weihai Liu
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
- Peking University Health Science Center, Beijing, 100191, China
| | - Yuwei Dai
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
- Peking University Health Science Center, Beijing, 100191, China
| | - Shikun Liu
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
- Peking University Health Science Center, Beijing, 100191, China
| | - Ke Ma
- Peking University Health Science Center, Beijing, 100191, China
| | - Guozhong Lin
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
| | - Jun Yang
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China
| | - Hongyi Liu
- Henan Academy of Innovations in Medical Science (AIMS), Zhengzhou, 450003, China
- National Engineering Research Center for Ophthalmology, Beijing, 100730, China
- Engineering Research Center of Ophthalmic Equipment and Materials, Ministry of Education, Beijing, 100730, China
- Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, 100730, China
| | - Jian Wu
- Henan Academy of Innovations in Medical Science (AIMS), Zhengzhou, 450003, China.
- National Engineering Research Center for Ophthalmology, Beijing, 100730, China.
- Engineering Research Center of Ophthalmic Equipment and Materials, Ministry of Education, Beijing, 100730, China.
- Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, 100730, China.
| | - Chenlong Yang
- Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China.
- Center for Precision Neurosurgery and Oncology of Peking University Health Science Center, Peking University, Beijing, 100191, China.
- Henan Academy of Innovations in Medical Science (AIMS), Zhengzhou, 450003, China.
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14
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Pan W, Huang W, Zheng J, Meng Z, Pan X. Construction of a prognosis model of head and neck squamous cell carcinoma pyroptosis and an analysis of immuno-phenotyping based on bioinformatics. Transl Cancer Res 2024; 13:299-316. [PMID: 38410218 PMCID: PMC10894328 DOI: 10.21037/tcr-23-922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/20/2023] [Indexed: 02/28/2024]
Abstract
Background Head and neck squamous cell carcinoma (HNSCC) is currently the sixth most common cancer worldwide, and its prevalence and recurrence rates are gradually increasing. To study the relationship between HNSCC and cell pyroptosis and provide new treatment options for HNSCC, a prognostic model of pyroptosis-related genes (PRGs) was established to predict the prognosis of patients with HNSCC, and an immune correlation analysis was performed. Methods A total of 53 PRGs were selected. We comprehensively analyzed the role of these PRGs in HNSCC through multiple omics data-set integration. We then identified two different molecular subtypes and found that changes in multi-layer PRGs were associated with clinicopathological characteristics, prognosis, and tumor microenvironment cell-infiltration characteristics in patients. Next, prognostic models were generated for nine PRGs; that is, cytotoxic T lymphocyte antigen 4 (CTLA4), V-set and immunoglobulin domain containing 4 (VSIG4), heparin-binding-epidermal growth factor (HBEGF), aquaporin-1 (AQP1), sodium channel epithelial 1 subunit delta (SCNN1D), argininosuccinate synthase 1 (ASS1), family with sequence similarity 83 member (FAM83), cyclin dependent kinase inhibitor 2A (CDKN2A), and serine protease inhibitor Kazal 6 (SPINK6). Finally, a risk-score model was constructed, and the Kaplan-Meier method was used to evaluate overall survival. In addition, the immune environment and drug sensitivity were analyzed. Results This study showed that pyroptosis is closely related to HNSCC. The scores generated by the risk markers based on the new nine PRGs were identified as independent risk factors for predicting HNSCC. The differentially expressed genes between the low- and high-risk groups were further found to be related to the tumor immune cells and pathways. In addition, the risk score was found to be significantly correlated with chemosensitivity. Conclusions Our comprehensive analysis of PRGs revealed their potential role in the tumor immune microenvironment, clinicopathological characteristics, and prognosis. These findings may improve our understanding of pyroptosis in HNSCC and may provide new ideas for evaluating prognosis and developing more effective immunotherapy strategies.
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Affiliation(s)
- Wenna Pan
- Department of Maxillofacial Surgery, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Wenbin Huang
- Department of Breast Care Surgery, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
- Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiajun Zheng
- Department of Neurosurgery, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zilu Meng
- Department of Maxillofacial Surgery, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
| | - Xuan Pan
- Department of Maxillofacial Surgery, The First Affiliated Hospital, Guangdong Pharmaceutical University, Guangzhou, China
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15
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Frumento D, Grossi G, Falesiedi M, Musumeci F, Carbone A, Schenone S. Small Molecule Tyrosine Kinase Inhibitors (TKIs) for Glioblastoma Treatment. Int J Mol Sci 2024; 25:1398. [PMID: 38338677 PMCID: PMC10855061 DOI: 10.3390/ijms25031398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/17/2024] [Accepted: 01/21/2024] [Indexed: 02/12/2024] Open
Abstract
In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15-16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials.
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Affiliation(s)
| | | | | | - Francesca Musumeci
- Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy; (D.F.); (G.G.); (M.F.); (S.S.)
| | - Anna Carbone
- Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy; (D.F.); (G.G.); (M.F.); (S.S.)
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Ji ZZ, Chan MKK, Chan ASW, Leung KT, Jiang X, To KF, Wu Y, Tang PMK. Tumour-associated macrophages: versatile players in the tumour microenvironment. Front Cell Dev Biol 2023; 11:1261749. [PMID: 37965573 PMCID: PMC10641386 DOI: 10.3389/fcell.2023.1261749] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/12/2023] [Indexed: 11/16/2023] Open
Abstract
Tumour-Associated Macrophages (TAMs) are one of the pivotal components of the tumour microenvironment. Their roles in the cancer immunity are complicated, both pro-tumour and anti-cancer activities are reported, including not only angiogenesis, extracellular matrix remodeling, immunosuppression, drug resistance but also phagocytosis and tumour regression. Interestingly, TAMs are highly dynamic and versatile in solid tumours. They show anti-cancer or pro-tumour activities, and interplay between the tumour microenvironment and cancer stem cells and under specific conditions. In addition to the classic M1/M2 phenotypes, a number of novel dedifferentiation phenomena of TAMs are discovered due to the advanced single-cell technology, e.g., macrophage-myofibroblast transition (MMT) and macrophage-neuron transition (MNT). More importantly, emerging information demonstrated the potential of TAMs on cancer immunotherapy, suggesting by the therapeutic efficiency of the checkpoint inhibitors and chimeric antigen receptor engineered cells based on macrophages. Here, we summarized the latest discoveries of TAMs from basic and translational research and discussed their clinical relevance and therapeutic potential for solid cancers.
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Affiliation(s)
- Zoey Zeyuan Ji
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Max Kam-Kwan Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Alex Siu-Wing Chan
- Department of Applied Social Sciences, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China
| | - Kam-Tong Leung
- Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Xiaohua Jiang
- Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Yi Wu
- MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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17
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Zhu Y, Wu M. Noninvasive radiomic analysis of enhanced CT predicts CTLA4 expression and prognosis in head and neck squamous cell carcinoma. Sci Rep 2023; 13:16782. [PMID: 37798374 PMCID: PMC10556051 DOI: 10.1038/s41598-023-43582-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 09/26/2023] [Indexed: 10/07/2023] Open
Abstract
Developing a radiomic model to predict CTLA4 expression levels and assessing its prognostic accuracy for patients. Medical imaging data were sourced from the TCIA database, while transcriptome sequencing data were derived from the TCGA database. We utilized a linear kernel SVM algorithm to develop a radiomic model for predicting CTLA4 gene expression. We then assessed the model's clinical relevance using survival and Cox regression analyses. Performance evaluations of the model were illustrated through ROC, PR, calibration, and decision curves. (1) Bioinformatics analysis: Kaplan-Meier curves indicated that increased CTLA4 expression correlates with enhanced overall survival (OS) (p < 0.001). Both univariate and multivariate analyses revealed that high CTLA4 expression served as a protective factor for OS (HR = 0.562, 95% CI 0.427-0.741, p < 0.001). (2) Radiomics evaluation: the ROC curve demonstrated that the AUC for the SVM radiomics model was 0.766 in the training set and 0.742 in the validation set. The calibration curve affirmed that the model's prediction probability for high gene expression aligns with the actual outcomes. Furthermore, decision curve analysis (DCA) indicated that our model boasts robust clinical applicability. CTLA4 expression level serves as an independent prognostic factor for HNSCCs. Using enhanced CT images, the SVM radiomic model effectively predicts CTLA4 expression levels. As a result, this model offers strong prognostic insights for HNSCCs, guiding precise diagnosis, treatment, and assisting in clinical decision-making.
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Affiliation(s)
- Yeping Zhu
- Nanjing University of Chinese Medicine, No. 282, Hanzhong Road, Nanjing, Jiangsu, China
| | - Mianhua Wu
- Nanjing University of Chinese Medicine, No. 282, Hanzhong Road, Nanjing, Jiangsu, China.
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18
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Vishnoi M, Dereli Z, Yin Z, Kong EK, Kinali M, Thapa K, Babur O, Yun K, Abdelfattah N, Li X, Bozorgui B, Rostomily RC, Korkut A. A prognostic matrix code defines functional glioblastoma phenotypes and niches. RESEARCH SQUARE 2023:rs.3.rs-3285842. [PMID: 37790408 PMCID: PMC10543369 DOI: 10.21203/rs.3.rs-3285842/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a "matrix code" for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better patient survival, respectively. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles provide potential biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification which could be applied to optimize treatment responses.
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Affiliation(s)
- Monika Vishnoi
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurosurgery, University of Washington School of Medicine, Seattle WA, 98195
| | - Zeynep Dereli
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zheng Yin
- Department of Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center, Houston, TX, 77030 USA
| | - Elisabeth K. Kong
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Statistics, Rice University, Houston, TX, 77030, USA
| | - Meric Kinali
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Kisan Thapa
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Ozgun Babur
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Kyuson Yun
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurology, Weill Cornell Medical School, New York NY, 10065
| | - Nourhan Abdelfattah
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurology, Weill Cornell Medical School, New York NY, 10065
| | - Xubin Li
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Behnaz Bozorgui
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert C. Rostomily
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurosurgery, University of Washington School of Medicine, Seattle WA, 98195
- Department of Neurosurgery, Weill Cornell Medical School, New York NY, 10065
| | - Anil Korkut
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
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19
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Das S, Dash BS, Premji TP, Chen JP. Immunotherapeutic Approaches for the Treatment of Glioblastoma Multiforme: Mechanism and Clinical Applications. Int J Mol Sci 2023; 24:10546. [PMID: 37445721 PMCID: PMC10341481 DOI: 10.3390/ijms241310546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/13/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Glioma is one of the most aggressive types of primary brain tumor with a high-grade glioma known as glioblastoma multiforme (GBM). Patients diagnosed with GBM usually have an overall survival rate of less than 18 months after conventional therapy. This bleak prognosis underlines the need to consider new therapeutic interventions for GBM treatment to overcome current treatment limitations. By highlighting different immunotherapeutic approaches currently in preclinical and clinical trials, including immune checkpoint inhibitors, chimeric antigen receptors T cells, natural killer cells, vaccines, and combination therapy, this review aims to discuss the mechanisms, benefits, and limitations of immunotherapy in treating GBM patients.
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Affiliation(s)
- Suprava Das
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan; (S.D.); (B.S.D.); (T.P.P.)
| | - Banendu Sunder Dash
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan; (S.D.); (B.S.D.); (T.P.P.)
| | - Thejas P. Premji
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan; (S.D.); (B.S.D.); (T.P.P.)
| | - Jyh-Ping Chen
- Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan; (S.D.); (B.S.D.); (T.P.P.)
- Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Kwei-San, Taoyuan 33305, Taiwan
- Craniofacial Research Center, Chang Gung Memorial Hospital at Linkou, Kwei-San, Taoyuan 33305, Taiwan
- Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Kwei-San, Taoyuan 33305, Taiwan
- Department of Materials Engineering, Ming Chi University of Technology, Tai-Shan, New Taipei City 24301, Taiwan
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20
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Sun Y, Li R, Chen Y, Yang B, Li X, Li Z, He J, Zhou Z, Li J, Guo X, Wang X, Wu Y, Zhang W, Guo G. The value of basement membrane-associated genes in the prognosis and immune regulation of glioma. Medicine (Baltimore) 2023; 102:e33935. [PMID: 37335645 PMCID: PMC10256338 DOI: 10.1097/md.0000000000033935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/15/2023] [Indexed: 06/21/2023] Open
Abstract
Gliomas have a high incidence rate in central nervous tumors. Although many breakthroughs have been made in the pathogenesis and treatment of glioma, the recurrence and metastasis rates of patients have not been improved based on the uniqueness of glioma. Glioma destroys the surrounding basement membrane (BM), leading to local infiltration, resulting in the corresponding clinical and neurological symptoms. Therefore, exploring the biological roles played by BM associated genes in glioma is particularly necessary for a comprehensive understanding of the biological processes of glioma and its treatment. Differential expression and univariate COX regression analyses were used to identify the basement membrane genes (BMGs) to be included in the model. LASSO regression was used to construct the BMG model. The Kaplan-Meier (KM) survival analysis model was used to assess the prognosis discrimination between training sets, validation sets, and clinical subgroups. Receiver-operating characteristic (ROC) analysis was used to test the prognostic efficacy of the model. Use calibration curves to verify the accuracy of nomograms. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG), and gene set enrichment analysis (GSEA) were used to analyze the function and pathway enrichment among the model groups. ESTIMATE and other 7 algorithms including CIBERSORT were used to evaluate the immune microenvironment. "pRRophetic" was used to evaluate drug sensitivity. This study demonstrated that high-risk genes (LAMB4, MMP1, MMP7) promote glioma progression and negatively correlate with patient prognosis. In the tumor microenvironment (TME), high-risk genes have increased scores of macrophages, neutrophils, immune checkpoints, chemokines, and chemokine receptors. This study suggests that BMGs, especially high-risk-related genes, are potential sites for glioma therapy, a new prospect for comprehensively understanding the molecular mechanism of glioma.
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Affiliation(s)
- Yanqi Sun
- Department of Emergency, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ren Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yang Chen
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Biao Yang
- Department of Emergency, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xuepeng Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ziao Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianhang He
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zihan Zhou
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jiayu Li
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaolong Guo
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaogang Wang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Yongqiang Wu
- Department of Emergency, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Wenju Zhang
- Department of Neurosurgery, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Geng Guo
- Department of Emergency, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
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21
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Vishnoi M, Dereli Z, Yin Z, Kong EK, Kinali M, Thapa K, Babur O, Yun K, Abdelfattah N, Li X, Bozorgui B, Rostomily RC, Korkut A. A prognostic matrix code defines functional glioblastoma phenotypes and niches. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.06.543903. [PMID: 37333072 PMCID: PMC10274725 DOI: 10.1101/2023.06.06.543903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a "matrix code" for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better survival, respectively, of patients. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles may provide biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification to optimize treatment responses.
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Affiliation(s)
- Monika Vishnoi
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurosurgery, University of Washington School of Medicine, Seattle WA, 98195
| | - Zeynep Dereli
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Zheng Yin
- Department of Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center, Houston, TX, 77030 USA
| | - Elisabeth K. Kong
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Statistics, Rice University, Houston, TX, 77030, USA
| | - Meric Kinali
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Kisan Thapa
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Ozgun Babur
- Computer Science, College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125
| | - Kyuson Yun
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurology, Weill Cornell Medical School, New York NY, 10065
| | - Nourhan Abdelfattah
- Department of Neurology, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurology, Weill Cornell Medical School, New York NY, 10065
| | - Xubin Li
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Behnaz Bozorgui
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Robert C. Rostomily
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, 77030 USA
- Department of Neurosurgery, University of Washington School of Medicine, Seattle WA, 98195
- Department of Neurosurgery, Weill Cornell Medical School, New York NY, 10065
| | - Anil Korkut
- Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
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22
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Rocha Pinheiro SL, Lemos FFB, Marques HS, Silva Luz M, de Oliveira Silva LG, Faria Souza Mendes dos Santos C, da Costa Evangelista K, Calmon MS, Sande Loureiro M, Freire de Melo F. Immunotherapy in glioblastoma treatment: Current state and future prospects. World J Clin Oncol 2023; 14:138-159. [PMID: 37124134 PMCID: PMC10134201 DOI: 10.5306/wjco.v14.i4.138] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/06/2023] [Accepted: 04/12/2023] [Indexed: 04/21/2023] Open
Abstract
Glioblastoma remains as the most common and aggressive malignant brain tumor, standing with a poor prognosis and treatment prospective. Despite the aggressive standard care, such as surgical resection and chemoradiation, median survival rates are low. In this regard, immunotherapeutic strategies aim to become more attractive for glioblastoma, considering its recent advances and approaches. In this review, we provide an overview of the current status and progress in immunotherapy for glioblastoma, going through the fundamental knowledge on immune targeting to promising strategies, such as Chimeric antigen receptor T-Cell therapy, immune checkpoint inhibitors, cytokine-based treatment, oncolytic virus and vaccine-based techniques. At last, it is discussed innovative methods to overcome diverse challenges, and future perspectives in this area.
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Affiliation(s)
- Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | | | | | - Mariana Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Matheus Sande Loureiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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23
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Wang Y, Liu Y, Zhang C, Zhang C, Guan X, Jia W. Differences of macrophages in the tumor microenvironment as an underlying key factor in glioma patients. Front Immunol 2022; 13:1028937. [PMID: 36389681 PMCID: PMC9659848 DOI: 10.3389/fimmu.2022.1028937] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/13/2022] [Indexed: 08/11/2024] Open
Abstract
BACKGROUND Macrophages, the major immune cells in glioma microenvironment, are closely related to tumor prognosis. Further studies are needed to investigate macrophages, which will be helpful to fully understand the role of it and early achieve clinical translation. METHODS A total of 1334 glioma cases were enrolled in this study from 3 databases. In our works, the single cell cohorts from GSE89567, GSE84465, and the Chinese Glioma Genome Atlas (CGGA) datasets were used to analyze the key genes of macrophage. The bulk sequencing data from the Cancer Genome Atlas (TCGA) and CGGA datasets were respectively divided into the training set and validation set to test prognostic value of the key genes from single cell analysis. RESULTS Quantitative and functional differences significantly emerge in macrophage clusters between LGG and GBM. Firstly, we used the Seurat R package to identify 281 genes differentially expressed genes in macrophage clusters between LGG and GBM. Furthermore, based on these genes, we developed a predictive risk model to predict prognosis and reflect the immune microenvironment in glioma. The risk score calculation formula was yielded as follows: Risk score = (0.11 × EXPMACC1) + (-0.31 × EXPOTUD1) + (-0.09 × EXPTCHH) + (0.26 × EXPADPRH) + (-0.40× EXPABCG2) + (0.21 × EXPPLBD1) + (0.12 × EXPANG) + (0.29 × EXPQPCT). The risk score was independently related to prognosis. Further, significant differences existed in immunological characteristics between the low- and high-risk score groups. What is more, mutation analysis found different genomic patterns associated with the risk score. CONCLUSION This study further confirms that the proportion of macrophage infiltration is not only significantly different, but the function of them is also different. The signature, identified from the differentially expressed macrophage-related genes impacts poor prognosis and short overall survival and may act as therapeutic targets in the future.
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Affiliation(s)
- Yangyang Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yan Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chengkai Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chuanbao Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiudong Guan
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wang Jia
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases (NCRC-ND), Beijing, China
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24
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Zeng L, Liu XY, Chen K, Qin LJ, Wang FH, Miao L, Li L, Wang HY. Phosphoserine phosphatase as an indicator for survival through potentially influencing the infiltration levels of immune cells in neuroblastoma. Front Cell Dev Biol 2022; 10:873710. [PMID: 36092735 PMCID: PMC9459050 DOI: 10.3389/fcell.2022.873710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 07/26/2022] [Indexed: 11/23/2022] Open
Abstract
Introduction: Metabolic deregulation, a hallmark of cancer, fuels cancer cell growth and metastasis. Phosphoserine phosphatase (PSPH), an enzyme of the serine metabolism pathway, has been shown to affect patients’ prognosis in many cancers but its significance in neuroblastoma remains unknown. Here, we show that the functional role and potential mechanism of PSPH and it is correlated with survival of neuroblastoma patients. Patients and Methods: The TARGET dataset (n = 151) and our hospital-based cases (n = 55) were used for assessing the expression level of PSPH associated with survival in neuroblastoma patients, respectively. Then, in vitro experiments were performed to define the role of PSPH in neuroblastoma. The ESTIMATE and TIMER algorithms were utilized to examine the correlation between PSPH expression level and abundance of immune cells. Further, Kaplan-Meier survival analysis was performed to evaluate the effect of both PSPH and immune cells on patients’ prognosis. Results: High expression of PSPH was significantly associated with unfavorable overall survival (OS) and event-free survival (EFS) in both the TARGET dataset and our hospital-based cases, and was an independent predictor of OS (hazard ratio, 2.00; 95% confidence intervals, 1.21–3.30, p = 0.0067). In vitro experiments showed that high expression of PSPH significantly promoted cell growth and metastasis. Further, the ESTIMATE result suggested that high expression level of PSPH was negatively associated with low stromal and ESTIMATE score. Specifically, high PSPH expression was found to be negatively associated with CD8+ T cell, macrophages and neutrophils, which negatively affected survival of neuroblastoma patients (p < 0.0001, p = 0.0005, and p = 0.0004, respectively). Conclusion: These findings suggested that PSPH expression could be a promising indicator for prognosis and immunotherapy in neuroblastoma patients by potentially influencing infiltration levels of immune cells.
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Affiliation(s)
- Liang Zeng
- Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
| | - Xiao-Yun Liu
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Kai Chen
- Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
| | - Liang-Jun Qin
- Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
| | - Feng-Hua Wang
- Departments of Thoracic Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
| | - Le Li
- Departments of Thoracic Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
| | - Hai-Yun Wang
- Department of Pathology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children’s Medical Center for South Central Region, Guangzhou, China
- *Correspondence: Hai-Yun Wang,
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25
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Wang J, Yang Y, Du B. Clinical Characterization and Prognostic Value of TPM4 and Its Correlation with Epithelial–Mesenchymal Transition in Glioma. Brain Sci 2022; 12:brainsci12091120. [PMID: 36138856 PMCID: PMC9497136 DOI: 10.3390/brainsci12091120] [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: 07/26/2022] [Revised: 08/19/2022] [Accepted: 08/21/2022] [Indexed: 11/26/2022] Open
Abstract
Tropomyosin 4 (TPM4) has been reported as an oncogenic gene across different malignancies. However, the role of TPM4 in glioma remains unclear. This study aimed to determine the clinical characterization and prognostic value of TPM4 in gliomas. Transcriptome expression and clinical information were collected from the CGGA and TCGA datasets, which included 998 glioma patients. ScRNA-seq data were obtained from CGGA. R software was utilized for statistical analyses. There was a positive correlation between TPM4 and WHO grades. IDH-wildtype and mesenchymal subtype gliomas were accompanied by TPM4 upregulation. GO and GSEA analysis suggested that TPM4 was profoundly associated with epithelial-to-mesenchymal transition (EMT). Subsequent GSVA revealed a robust correlation between TPM4 and three signaling pathways of EMT (hypoxia, TGF-β, PI3K/AKT). Furthermore, TPM4 showed a synergistic effect with mesenchymal biomarkers, particularly with N-cadherin, Slug, Snail, TWIST1, and vimentin. ScRNA-seq analysis suggested that higher TPM4 was mainly attributed to tumor cells and macrophages and associated with tumor cell progression and macrophage polarization. Finally, high TPM4 was significantly associated with unfavorable outcomes. In conclusion, our findings indicate that TPM4 is significantly correlated with more malignant characteristics of gliomas, potentially through involvement in EMT. TPM4 could predict worse survival for patients with glioma.
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Affiliation(s)
- Jin Wang
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University), Shenzhen 518020, China
| | - Ying Yang
- Department of Pediatrics, Futian Women and Children Health Institute, Shenzhen 518045, China
| | - Bo Du
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University), Shenzhen 518020, China
- Correspondence: ; Tel.: +86-159-1414-1979
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26
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Aisa A, Tan Y, Li X, Zhang D, Shi Y, Yuan Y. Comprehensive Analysis of the Brain-Expressed X-Link Protein Family in Glioblastoma Multiforme. Front Oncol 2022; 12:911942. [PMID: 35860560 PMCID: PMC9289282 DOI: 10.3389/fonc.2022.911942] [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: 04/03/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common, malignant, and deadly primary brain tumor in adults. Brain-expressed X-link (BEX) protein family is involved in tumorigenesis. Here, we have explored the biological function and the prognostic value of the BEX family in GBM. Differentially expressed BEX genes between GBM and normal tissue were screened by using The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses identified the prognosis‐related genes BEX1, BEX2, and BEX4, which were involved in the regulation of immune response. The results of correlation analysis and protein–protein interaction network (PPI network) showed that there was a significant correlation between the BEX family and TCEAL family in GBM. Furthermore, the expression of transcription elongation factor A (SII)-like (TCEAL) family is generally decreased in GBM and related to poor prognosis. With the use of the least absolute shrinkage and selection operator (LASSO) Cox regression, a prognostic model including the BEX family and TCEAL family was built to accurately predict the likelihood of overall survival (OS) in GBM patients. Therefore, we demonstrated that the BEX family and TCEAL family possessed great potential as therapeutic targets and prognostic biomarkers in GBM. Further investigations in large‐scale, multicenter, and prospective clinical cohorts are needed to confirm the prognostic model developed in our study.
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Affiliation(s)
- Adilai Aisa
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yinuo Tan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Xinyu Li
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Ding Zhang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yun Shi
- Nursing Department, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- *Correspondence: Ying Yuan,
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