Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Oct 26;13(10):1417-1445.
doi: 10.4252/wjsc.v13.i10.1417.

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Milena Stevanovic  1 , Natasa Kovacevic-Grujicic  1 , Marija Mojsin  1 , Milena Milivojevic  1 , Danijela Drakulic  1
Affiliations
Review

SOX transcription factors and glioma stem cells: Choosing between stemness and differentiation

Milena Stevanovic et al. World J Stem Cells. .

Abstract

Glioblastoma (GBM) is the most common, most aggressive and deadliest brain tumor. Recently, remarkable progress has been made towards understanding the cellular and molecular biology of gliomas. GBM tumor initiation, progression and relapse as well as resistance to treatments are associated with glioma stem cells (GSCs). GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types, generating a range of distinct cell types within the tumor, leading to cellular heterogeneity. GBM tumors may contain different subsets of GSCs, and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy. GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties, making them more malignant, able to rapidly spread. The impact of SOX transcription factors (TFs) on brain tumors has been extensively studied in the last decade. Almost all SOX genes are expressed in GBM, and their expression levels are associated with patient prognosis and survival. Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation. The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation. Therefore, innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM. Combatting GBM has been a demanding and challenging goal for decades. The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival. Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.

Keywords: Differentiation; Glioblastoma; Glioma stem cells; SOX transcription factors; Stemness.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest statement: The authors declare no conflict of interest for this article.

Figures

Figure 1
Figure 1
Historical overview of the hallmarks of cancer. Hallmarks of cancer proposed by Hanahan and Weinberg[1,2] in 2000 and 2011 are presented in yellow and blue colors, respectively. Additional hallmarks of cancer proposed by Senga and Grose[3] in 2021 are presented in pink.
Figure 2
Figure 2
The roles of the SOX2 transcription factor in cancer. Modified from[223].
Figure 3
Figure 3
Potential cells of origin of glioblastoma. During the neural differentiation process (black arrows), neural stem cells differentiate into fate-restricted precursors that are capable of differentiating into neurons, astrocytes or oligodendrocytes. Glioblastoma cells can arise due to the accumulation of cancer driver mutations in different cell types or due to the dedifferentiation of mature cells (orange arrows). Modified from[224]. References are included in the main text.
Figure 4
Figure 4
Signaling pathways involved in the maintenance of glioma stem cell properties. The main signaling pathways involved in the maintenance of glioma stem cell properties include Hedgehog, Wnt/β-catenin, NOTCH, Epidermal growth factor receptor, Phosphatidylinositol-3-phosphate kinase/AKT/Mammalian target of rapamycin, Mitogen-activated protein kinase, Inhibitory kappa B kinase/Nuclear factor-kappa B, Transforming growth factor-beta/Small mothers against decapentaplegic and Janus kinase/Signal transducers and activators of transcription. References are included in the main text. MAPK: Mitogen-activated protein kinase; JAK/STAT: Janus kinase/Signal transducers and activators of transcription; EGFR: Epidermal growth factor receptor; PI3K/AKT/mTOR: Phosphatidylinositol-3-phosphate kinase/AKT/Mammalian target of rapamycin; IKK/NF-κB: Inhibitory kappa B kinase/Nuclear factor-kappa B; TGF-β/SMAD: Transforming growth factor-beta/Small mothers against decapentaplegic; GSCs: Glioma stem cells.
Figure 5
Figure 5
The roles of SOX transcription factors in glioma stem cells. SOX transcription factors exert numerous functions in glioma stem cells (GSCs). They influence GSC self-renewal, stemness, tumorigenicity, sphere-forming capacity, proliferation rate, viability, migration and invasion capacities, and apoptosis. Some of the members of the SOX gene family are involved in the resistance of GSCs to therapy. Blue arrows represent stimulation, and orange bars represent inhibition. References are included in the main text. GSCs: Glioma stem cells.
Figure 6
Figure 6
SOX transcription factors involved in the maintenance of stemness and differentiation of glioma stem cells. References are included in the main text.
Figure 7
Figure 7
Mechanisms of chemo- and radioresistance of glioma stem cells. A: O6-methylguanine-DNA methyltransferase (MGMT) repair; B: Overexpression of drug efflux transporters; C: Enhanced antiapoptotic pathway; D: Increased replicative stress and DNA damage response. Efficient DNA repair; E: Dysregulated signaling pathways; F: Proneural-to-mesenchymal transition; G: Dedifferentiation to GSC; H: Glioma stem cells (GSC) quiescence. Resistance of GSCs to temozolomide is achieved through increased expression of MGMT, drug efflux transporters and antiapoptotic proteins. Replicative stress, constitutively active DNA damage response and efficient DNA repair confer radioresistance to GSCs. Aberrantly activated signaling pathways, the ability of non-GSC tumor cells to dedifferentiate, proneural-to-mesenchymal transition and the capacity of GSCs to become quiescent contribute to the chemo- and radioresistance of glioblastoma. References are included in the main text. RT: radiation; O6-MeG: O-6-methylguanine; GSC: Glioma stem cell; TMZ: Temozolomide.
Figure 8
Figure 8
Schematic illustration of the involvement of SOX2 and SOX9 in the chemoresistance and radioresistance of glioma stem cells. The expression of stemness-related transcription factor SOX2 is elevated in glioma stem cells (GSCs) through various mechanisms (decreased expression of miR-145 and miR-9* that directly target SOX2, direct transcriptional activation by Forkhead box M1 and through mammalian target of rapamycin signaling) contributing to chemo- and radioresistance of GSCs. SOX2 directly activates the expression of ABCC3 and ABCC6 transporters. mTOR signaling affects the SOX2/SOX9 axis, contributing to chemoresistance. The ERK1/2/miR-124/SOX9 axis and direct targeting of PDK1 (pyruvate dehydrogenase kinase 1) by SOX9 have a role in resistance to radiation and temozolomide, respectively. References are included in the main text. GSCs: Glioma stem cells; FOXM1: Forkhead box M1; mTOR: Mammalian target of rapamycin; PDK1: Pyruvate dehydrogenase kinase 1.
Figure 9
Figure 9
Overview of the therapeutic strategies for targeting SOX in glioma stem cells. References are included in the main text. GSCs: Glioma stem cells.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. - PubMed
    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. - PubMed
    1. Negrini S, Gorgoulis VG, Halazonetis TD. Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11:220–228. - PubMed
    1. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30:1073–1081. - PubMed
    1. DeNardo DG, Andreu P, Coussens LM. Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Rev. 2010;29:309–316. - PMC - PubMed