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Glioblastoma Stem Cells and Wnt Signaling Pathway: Molecular Mechanisms and Therapeutic Targets Ruoyu Guan1, Xiaoming Zhang2 and Mian Guo1*

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Glioblastoma Stem Cells and Wnt Signaling Pathway: Molecular Mechanisms and Therapeutic Targets Ruoyu Guan1, Xiaoming Zhang2 and Mian Guo1* Guan et al. Chinese Neurosurgical Journal (2020) 6:25 https://doi.org/10.1186/s41016-020-00207-z 中华医学会神经外科学分会 CHINESE MEDICAL ASSOCIATION CHINESE NEUROSURGICAL SOCIETY REVIEW Open Access Glioblastoma stem cells and Wnt signaling pathway: molecular mechanisms and therapeutic targets Ruoyu Guan1, Xiaoming Zhang2 and Mian Guo1* Abstract Glioblastoma is the most common form of primary brain tumor. Glioblastoma stem cells play an important role in tumor formation by activation of several signaling pathways. Wnt signaling pathway is one such important pathway which helps cellular differentiation to promote tumor formation in the brain. Glioblastoma remains to be a highly destructive type of tumor despite availability of treatment strategies like surgery, chemotherapy, and radiation. Advances in the field of cancer biology have revolutionized therapy by allowing targeting of tumor-specific molecular deregulation. In this review, we discuss about the significance of glioblastoma stem cells in cancer progression through Wnt signaling pathway and highlight the clinical targets being potentially considered for therapy in glioblastoma. Background are two Wnt pathways which determine the cell fate. Glioblastoma also known as glioblastoma multiforme Canonical Wnt signaling pathway is essential for embry- (GBM) is one of the most lethal and commonly identified onic development [10] and non-canonical Wnt pathway forms of brain tumor [1]. Around 80% of the GBM tumors regulates cell movement and tissue polarity [11]. are located in the cerebral hemisphere (< 5%) located in The current review focuses on the importance of Wnt the cerebellum, brain stem, and spinal cord [2]. GBM are signaling pathway in glioblastoma stem cell progression malignant tumors commonly seen in 40–60-year-old indi- and explores targeting of Wnt signaling molecules as a viduals [3]. GBMs are often characterized by presence of potential therapy for glioblastoma. glioblastoma stem cells (GSCs) [4], which are known to maintain their stemness through a number of signaling Glioblastoma stem cells pathways [5, 6]. One of pathways gaining attention in Glioblastoma stem cells (GSCs) can differentiate into dif- GBM is the Wnt signaling. Wnt deregulation in brain is ferent cell types [12]. GSCs contribute to tumor growth associated with congenital disorders [7], whereas it pro- and therapeutic resistance through multiple genetic and motes malignancy in somatic cells of neuronal origin [8]. epigenetic modifications [4, 13–15]. Genetic modification Wnt signaling pathway is mediated by Wnt family of 19 in GSCs are observed in the form of promotion of angio- secreted glycoproteins (bearing22 or 24 cysteine residues) genesis [16], promotion of hypoxia through HIF signaling which are essential for cell proliferation, embryonic devel- pathway [17], overexpression of surface marker such as opment, cell polarity, and tissue homeostasis [9]. There SALL4 to inhibit apoptosis [18], or maintenance of multi- potency through STAT3 regulation [19]. On the other * Correspondence: [email protected] hand, epigenetic modifications are also reported to be es- 1 Department of Neurosurgery, The Second Affiliated Hospital of Harbin sential for proliferation and survival of GSCs [20]. Hyper- Medical University, 246 Xuefu Road, Nangang, Harbin 150086, Heilongjiang Province, China methylation of specific genes are reportedly responsible Full list of author information is available at the end of the article for maintenance of stemness, GSC survival, faster GSC © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Guan et al. Chinese Neurosurgical Journal (2020) 6:25 Page 2 of 6 growth, and tumor promotion [21]. Additionally, several cell polarity pathway involved in cellular polarity. Bind- miRNAs are reported to induce invasion, migration, self- ing of wnt to FZD via DVL, JNK kinase activates the renewal, stemness, and proliferation in GSCs [22]. pathway responsible for changes in cytoskeleton [50]. The second non-canonical pathway is Ca2+-mediated Glioblastoma stem cells and their resistance to pathway where binding of wnt protein to FZD receptors chemotherapy and radiotherapy activates DVL and phospholipase C (PLC) followed by Chemotherapy and radiotherapy are commonly used ad- activation of inositol 1,4,5-triphosphate (IP3). IP3 inter- juvant therapies in GBM patients who have undergone acts with Ca2+ channels in the endoplasmic reticulum surgery. Despite treatment advances, GBM is associated and initiates the release of Ca2+ ions followed by activa- with high recurrence and reduced time for patient sur- tion of protein kinase C and cdc42, CAMKII, TAK1, vival [23]. GSCs are implicated for recurrence due to re- NLK, and NFAT [51–53]. sistance to therapy, thereby allowing cell renewal and tumor re-initiation, while physically, GSCs are difficult Role of Wnt signaling pathway in glioblastoma and to target because of their presence in the perivascular development of glioblastoma stem cells space [24]. At the molecular level, however, resistance to Aberrant Wnt signaling is found in various types of can- chemo- and radiotherapy is mediated through an aber- cers. Activation of Wnt pathway is these tumors may be rant expression of genes responsible for mismatch/base associated with mutations in sentinel components of the excision repair [25]. Additionally, the role of overex- pathway viz, APC, β-catenin, AXIN, WTX, and TCF4. pressed ABC transporters [26] chromatin remodeling Wnt signaling mutations are most extensively character- [27] and epigenetic modifications at the transcriptional ized in colorectal cancers. It has been observed that level have also been postulated [28]. close to 85% of colorectal tumors has a loss-of-function The GSC-associated resistance to therapy in GBM is mutation in APC whereas 50% of colorectal tumors addressed through a triaged approach: one which physic- which lack an APC mutation have activating mutation in ally allows drug targets to effectively reach the cells β-catenin. Mutations in Wnt signaling components of through change in tumor microenvironment [29–33], colon cancer and medulloblastoma were found to be second which targets GSCs [34, 35] or makes GSCs localized in β-catenin, APC, and AXIN1. Mutations of more susceptible to therapy [36–41], and third through Wnt components are well characterized in various other epigenetic modification in GSCs allowing change in cancers including hepatocellular carcinoma. Contrast- tumor characteristics [42–45] such as reduced sphere ingly, aberration of main components of Wnt pathway is formation, induction of cellular apoptosis, and preven- not of common occurrence in GBM, ovarian, head and tion of cellular proliferation. neck, breast, and gastric cancers [54, 55]. However, re- cent reports from a small cohort have reported APC Wnt signaling pathway mutations in about 13% of GBM cases with a mutation Canonical Wnt signaling pathway and non-canonical Wnt frequency of close to 14.5% [56]. Another independent signaling pathway study identified a homozygous deletion in a negative Wnt signaling is known as an important regulator of regulator of Wnt pathway, namely, FAT atypical cad- intercellular interaction, cell fate decision, and migration. herin 1 (FAT1) [55]. While the role of FAT 1 in GBMs Developmental defects are attributed to mutations in the has been explored previously via the PDCD4 [57] and critical components of Wnt signaling whereas aberrant the HIF-1α pathway [58], the study by Morris et al. [55] Wnt signaling is associated with cancers. Canonical Wnt was the first to demonstrate the influence of FAT1 dele- components bind to cell surface receptors namely friz- tion on Wnt activation. zled receptor (FZD) and activate low-density lipoprotein A recent study pointed to the role of proline-, glutamic receptor-related protein 5, 6 (LRP5/6) complex. Activa- acid-, and leucine-rich protein 1 (PELP1), a co-regulator tion of these receptors leads to destabilization of com- of several nuclear receptor proteins, activating β- plex consisting of adenomatous polyposis coli (APC), Catenin, thereby activating the Wnt signaling pathway. glycogen synthase kinase-3 (GSK3), and Axin [46]. This Overexpression of PELP1 was observed in 100 % of the stabilizes β-catenin, which then travels to nucleus, com- GBM samples [59]. plexes with T cell factor/lymphocyte enhancer factor, In addition to the mutations in the main components and activates Wnt target genes namely, c-myc, cyclin-D, constituting the Wnt pathway, few studies have
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