Systematic Reviews
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. May 26, 2024; 16(5): 604-614
Published online May 26, 2024. doi: 10.4252/wjsc.v16.i5.604
Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments
Edoardo Agosti, Marco Zeppieri, Mattia Ghidoni, Tamara Ius, Alessandro Tel, Marco Maria Fontanella, Pier Paolo Panciani
Edoardo Agosti, Mattia Ghidoni, Marco Maria Fontanella, Pier Paolo Panciani, Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia 25123, Italy
Marco Zeppieri, Department of Ophthalmology, University Hospital of Udine, Udine 33100, Italy
Tamara Ius, Neurosurgery Unit, Department of Head-Neck and NeuroScience, University Hospital of Udine, Udine 33100, Italy
Alessandro Tel, Clinic of Maxillofacial Surgery, Department of Head-Neck and NeuroScience, University Hospital of Udine, Udine 33100, Italy
Author contributions: Agosti E did the research and wrote the paper; Zeppieri M assisted in the conception and design of the study, writing, outline, and completed the English and scientific editing (a native English-speaking MD, Ph.D); Ghidoni M, Ius T, Tel A, Fontanella MM, and Panciani PP assisted in the outline of the draft, writing of the paper, research, editing of the paper; and all authors provided the final approval of the version of the article.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Marco Zeppieri, MD, PhD, Doctor, Department of Ophthalmology, University Hospital of Udine, p.le S. Maria della Misericordia 15, Udine 33100, Italy. mark.zeppieri@asufc.sanita.fvg.it
Received: December 23, 2023
Revised: March 6, 2024
Accepted: April 19, 2024
Published online: May 26, 2024
Processing time: 152 Days and 15.5 Hours
Abstract
BACKGROUND

Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy. Glioma stem cells (GSCs), a subset within tumors, contribute to resistance, tumor heterogeneity, and plasticity. Recent studies reveal GSCs’ role in therapeutic resistance, driven by DNA repair mechanisms and dynamic transitions between cellular states. Resistance mechanisms can involve different cellular pathways, most of which have been recently reported in the literature. Despite progress, targeted therapeutic approaches lack consensus due to GSCs’ high plasticity.

AIM

To analyze targeted therapies against GSC-mediated resistance to radio- and chemotherapy in gliomas, focusing on underlying mechanisms.

METHODS

A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to September 30, 2023. The search strategy utilized relevant Medical Subject Heading terms and keywords related to including “glioma stem cells”, “radiotherapy”, “chemotherapy”, “resistance”, and “targeted therapies”. Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated resistance to radiotherapy resistance (RTR).

RESULTS

In a comprehensive review of 66 studies on stem cell therapies for SCI, 452 papers were initially identified, with 203 chosen for full-text analysis. Among them, 201 were deemed eligible after excluding 168 for various reasons. The temporal breakdown of studies illustrates this trend: 2005-2010 (33.3%), 2011-2015 (36.4%), and 2016-2022 (30.3%). Key GSC models, particularly U87 (33.3%), U251 (15.2%), and T98G (15.2%), emerge as significant in research, reflecting their representativeness of glioma characteristics. Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) (27.3%) and Notch (12.1%) pathways, suggesting their crucial roles in resistance development. Targeted molecules with mTOR (18.2%), CHK1/2 (15.2%), and ATP binding cassette G2 (12.1%) as frequent targets underscore their importance in overcoming GSC-mediated resistance. Various therapeutic agents, notably RNA inhibitor/short hairpin RNA (27.3%), inhibitors (e.g., LY294002, NVP-BEZ235) (24.2%), and monoclonal antibodies (e.g., cetuximab) (9.1%), demonstrate versatility in targeted therapies. among 20 studies (60.6%), the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance (51.5%), followed by reductions in carmustine resistance (9.1%) and doxorubicin resistance (3.0%), while resistance to RTR is reduced in 42.4% of studies.

CONCLUSION

GSCs play a complex role in mediating radioresistance and chemoresistance, emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Keywords: Glioma stem cells, Chemoresistance, Radioresistance, Molecular pathways, Targeted therapies, Systematic review

Core Tip: The challenge of treating gliomas persists despite advancements in chemotherapy and radiotherapy, with glioma stem cells (GSCs) contributing to resistance and tumor heterogeneity. This systematic literature review, covering 66 studies, underscores the intricate role of GSCs in therapeutic resistance, particularly highlighting their involvement in DNA repair mechanisms and dynamic cellular state transitions. Targeted therapies face challenges due to GSCs’ high plasticity, and the review emphasizes the need for precision treatments that account for GSC population heterogeneity and the tumor microenvironment’s dynamic nature. Versatile therapeutic agents, including RNA inhibitor/short hairpin RNA, inhibitors (e.g., LY294002, NVP-BEZ235), and monoclonal antibodies (e.g., cetuximab), demonstrate efficacy in overcoming GSC-mediated resistance. Notably, the most common effect on the chemo- and radiotherapy response is a reduction in temozolomide resistance, highlighting the potential for improved outcomes by disrupting GSC-mediated resistance mechanisms in glioblastoma patients.