Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

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 re-sistance 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.

MiR-181b suppresses proliferation of and reduces chemoresistance to temozolomide in U87 glioma stem cells

MicroRNAs regulate self renewal and differentiation of cancer stem cells.There,we sought to identify the expression of miR-181b in glioma stem cells and investigate the biological effect of miR-181b on glioma stem cells in this study.MiR-181b expression was measured by real-time PCR in glioma stem cells isolated from U87 cells by FACS sorting.After miR-181b was overexpressed in U87 glioma stem cells by miR-181b lentiviral expression vector and/or treatment of temozolomide,secondary neurosphere assay,soft agar colony assay and MTT assay were performed.Compared with U87 cells,the expression of miR-181b was significantly decreased in U87 glioma stem cells.Overexpression of miR-181b decreased neurosphere formation by U87 glioma stem cells in vitro and suppressed colony formation in soft agar,and the cell growth inhibition rates increased in a time-dependent manner in U87 glioma stem cells infected with miR-181b lentivirus.Furthermore,miR-181b had a synergistic effect on temozolomide-induced inhibition of secondary neurosphere and soft agar colony,and on cell growth inhibition rates.MiR-181b functions as a tumor suppressor that suppresses proliferation and reduces chemoresistance to temozolomide in glioma stem cells.

Research on human glioma stem cells in China

Research on human glioma stem cells began early in the 21st century and since then has become a rapidly growing research field with the number of publications increasing year by year. The research conducted by our diverse group of investigators focused primarily on cell culture techniques, molecular regulation, signaling pathways, cancer treatment, the stem cell microenvironment and the cellular origin and function of glioma stem cells. In particular, we put forward our view that there are inverse or forward transformations among neural stem cells, glial cells and glioma stem cells in glioma tissues under certain conditions. Based on the background of the progress of international research on human glioma stem cells, we aim to share our progress and current findings of human glioma stem cell research in China with colleagues around the world.

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

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.

Isolation,cultivation and identification of brain glioma stem cells by magnetic bead sorting

This study describes a detailed process for obtaining brain glioma stem cells from freshly dissected human brain glioma samples using an immunomagnetic bead technique combined with serum-free media pressure screening. Furthermore, the proliferation, differentiation and self-renewal biological features of brain glioma stem cells were identified. Results showed that a small number of CD133 positive tumor cells isolated from brain glioma samples survived as a cell suspension in serum-free media and proliferated. Subcultured CD133 positive cells maintained a potent self-renewal and proliferative ability, and expressed the stem cell-specific markers CD133 and nestin. After incubation with fetal bovine serum, the number of glial fibrillary acidic protein and microtubule associated protein 2 positive cells increased significantly, indicating that the cultured brain glioma stem cells can differentiate into astrocytes and neurons. Western blot analysis showed that tumor suppressor phosphatase and tensin homolog was highly expressed in tumor spheres compared with the differentiated tumor cells. These experimental findings indicate that the immunomagnetic beads technique is a useful method to obtain brain glioma stem cells from human brain tumors.

The top cited articles on glioma stem cells in Web of Science

BACKGROUND： Glioma is the most common intracranial tumor and has a poor patient prognosis. The presence of brain tumor stem cells was gradually being understood and recognized, which might be beneficial for the treatment of glioma. OBJECTIVE： To use bibliometric indexes to track study focuses on glioma stem cell, and to investigate the relationships among geographic origin, impact factors, and highly cited articles indexed in Web of Science. METHODS： A list of citation classics for glioma stem cells was generated by searching the database of Web of Science-Expanded using the terms ＂glioma stem cell＂ or ＂glioma, stem cell＇＂ or ＂brain tumor stem cell＂. The top 63 cited research articles which were cited more than 100 times were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information on subject categories, country of origin, journals, authors, and source of journals. Inclusive criteria： （1） articles in the field of glioma stem cells which was cited more than 100 times; （2） fundamental research on humans or animals, clinical trials and case reports; （3） research article; （4） year of publication： 1899-2012; and （5） citation database： Science Citation Index-Expanded. Exclusive criteria： （1） articles needing to be manually searched or accessed only by telephone; （2） unpublished articles; and （3） reviews, conference proceedings, as well as corrected papers. RESULTS： Of 2 040 articles published, the 63 top-cited articles were published between 1992 and 2010. The number of citations ranged from 100 to 1 754, with a mean of 280 citations per article. These citation classics came from nineteen countries, of which 46 articles came from the United States. Duke University and University of California, San Francisco led the list of classics with seven papers each. The 63 top-cited articles were published in 28 journals, predominantly Cancer Research and Cancer Cell, followed by Cell Stem Cell and Nature. CONCLUSION： Our bibliometric analysis provides a historical perspective on the progress of glioma stem cell research. Articles originating from outstanding institutions of the United States and published in high-impact journals are most likely to be cited.

Glioma stem cells and the occurrence of tumor blood vessels

Epithelial glioma is the most common brain cancer,accounting for 35.26%-60.69%of intracranial tumors with an average of 44.69%,and it remains the greatest challenge in the field of neurosurgery.The median survival time of patients with advanced glioma is only 12 to 18 months due to the characteristics of high aggression,and the therapeutic effect was poor though surgery,chemotherapy,and targeted drug therapy being treated.Because of the presence of heterogeneity and the differentiation disorder,only a small number of glioma cells are the source of tumor growth and metastasis,which are highly resistant to traditional treatments.They are deemed as the“seed”tumor cells as they could get rid of the effect of the treatment and reconstruct the organization of tumor.They are also termed as brain tumor stem cell(BTSC)or glioma stem cells(GSCs)since neural stem cells share similar features with them.Recent data reveal that they are directly related with invasion,angiogenesis,tolerance,chemotherapy,recurrence of glioma.Based on the research result by the team,the paper elaborates the characteristics of GSCs and the relationship with the tumor angiogenesis.

Targeting glioma stem cells： enough to terminate gliomagenesis？

Objective To review the leading roles of glioma stem cells （GSCs） and their sophisticated interactions with other cells in the tissue remodeling process of gliomagenesis. Data sources Published articles about assessing GSCs in tumor initiation, progression, and multiple interactions with other cells in the special microenvironment were selected using PubMed. The search terms were ＂glioma stem cells＂, ＂tumorigenesis＂, and ＂microenvironment＂. Study selection Articles regarding the tissue remodeling of GSCs in gliomagenesis were selected. Results GSCs exhibit enhanced tumor-initiating ability, could reestablish tumor, and were resistant to radiotherapy and chemotherapy. Studying the role of GSCs in gliomagenesis helps to develop targeting therapy against GSCs, which seems to be a cure for gliomas. However, sophisticated interactions between GSCs and their local microenvironment during tumor remodeling, including integrating with partially differentiated tumor cells, GSCs niche, neural stem cells （NSCs）, normal glia, tumor-infiltrating lymphocytes, may obscure the leading role of GSCs during gliomagenesis, and make single targeting therapy unsuccessful. Conclusions Understanding the biological behavious of GSCs and their regulatory mechanisms may directly impact current efforts for more directed therapeutics against the highly aggressive gliomas. For multiple possible sources to turning into GSCs, simply eradicating the existing GSCs is not enough to be a cure for gliomas, blocking the potential sources of GSCs and ameliorating the local tumor inducing/promoting microenvironment should be a reasonable strategy.

Glioma stem cells and neural stem cells respond differently to BMP4 signaling

Malignant glioma is a highly heterogeneous and invasive primary brain tumor characterized by high recurrence rates,resistance to combined therapy,and dismal prognosis.Glioma stem cells(GSCs)are likely responsible for tumor progression,resistance to therapy,recurrence,and poor prognosis owing to their high self-renewal and tumorigenic potential.As a family member of BMP signaling,bone morphogenetic protein4(BMP4)has been reported to induce the differentiation of GSCs and neural stem cells(NSCs).However,the molecular mechanisms underlying the BMP4-mediated effects in these two cell types are unclear.In this study,we treated hGSCs and hNSCs with BMP4 and com-pared the phenotypic and transcriptional changes between these two cell types.Phenotypically,we found that the growth of hGSCs was greatly inhibited by BMP4,but the same treatment only increased the cell size of hNSCs.While the RNA sequencing results showed that BMP4 treatment evoked significantly transcriptional changes in both hGSCs and hNSCs,the profiles of differentially expressed genes were distinct between the two groups.A gene set that specifically targeted the proliferation and differentiation of hGSCs but not hNSCs was enriched and then validated in hGSC culture.Our results suggested that hGSCs and hNSCs responded differently to BMP4 stimulation.Understanding and investigating different responses between hGSCs and hNSCs will benefit finding partner factors working together with BMP4 to further suppress GSCs proliferation and stemness without disturbing NSCs.

Enhanced invasion in vitro and the distribution patterns in vivo of CD133＋ glioma stem cells

Background Recent studies have suggested that cancer stem cells cause tumor recurrence based on their resistance to radiotherapy and chemotherapy. Although the highly invasive nature of glioblastoma cells is also implicated in the failure of current therapies, it is not clear whether cancer stem cells are involved in invasiveness. This study aimed to assess invasive ability of glioma stem cells （GSCs） derived from C6 glioma cell line and the distribution patterns of GSCs in Sprague-Dawley （SD） rat brain tumor. Methods Serum-free medium culture and magnetic isolation were used to gain purely CD133＋ GSCs. The invasive ability of CD133＋ and CD133- C6 cells were determined using matrigel invasion assay. Immunohistochemical staining for stem cell markers and luxol fast blue staining for white matter tracts were performed to show the distribution patterns of GSCs in brain tumor of rats and the relationship among GSCs, vessels, and white matter tracts. The results of matrigel invasion assay were estimated using the Student＇s t test and the analysis of Western blotting was performed using the one-way analysis of variance （ANOVA） test. Results CD133＋ GSCs （number： 85.3±4.0） were significantly more invasive in vitro than matched CD133- cells （number： 25.9=~3.1） （t=14.5, P 〈0.005）. GSCs invaded into the brain diffusely and located in perivascular niche of tumor-brain interface or resided within perivascular niche next to white fiber tracts. The polarity of glioma cells containing GSCs was parallel to the white matter tracts. Conclusions Our data suggest that CD133＋ GSCs exhibit more aggressive invasion in vitro and GSCs in vivo probably disseminate along the long axis of blood vessels and transit through the white matter tracts. The therapies targeting GSCs invasion combined with traditional glioblastoma multiforme therapeutic paradigms might be a new approach for avoiding mali qnant glioma recurrence.

Experimental study on dendritic cells pulsed with brain tumor stem cells for immunotherapy of glioma

Objective To investigate the effect of dendritic cells pulsed with brain tumor stem cells which are used to treat on intracranial glioma. Methods We obtained murine brain tumor stem cells by grow ing C6 cells in epidermal grow th factor/basic fibroblast grow th factor w ithout serum.Dendritic cells isolated from rat bone marrow w ere pulsed w ith BTSCs. Rat brain

The Anticancer Activities Phenolic Amides from the Stem of Lycium barbarum

Four new phenolic amides,4-O-methylgrossamide(1),(E)-2-(4,5-dihydroxy-2-{3-[(4-hydrox-yphenethyl)amino]-3-oxopropyl}-phenyl)-3-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenethyl)acryl-amide(2),(Z)-lyciumamide C(3),(Z)-thoreliamide B(4),together with thirteen known phenolic amides were identified from the stem of Lycium barbarum.The structures of the new compounds were determined by spectroscopic methods.All compounds were evaluated for their anti-cancer activities against human glioma stem cell lines.

Downregulation of lncRNA-HOXA11-AS modulates proliferation and stemness in Glioma cells

Background: Glioma stem cells (GSCs) represent a subpopulation of cells within glioma that are characterized by chemotherapy resistance and tumor recurrence. GSCs are therefore important therapeutic target for glioma therapy.Long non-coding RNAs (lncRNAs) have been shown to regulate important functions in cancer. HOXA11-AS is one such lncRNA and has been shown to regulate cell proliferation via promotion of cell cycle progression in glioblastoma (GBM) cells. However, the specific roles of HOXA11-AS in GSCs remain unclear.Methods: Here we investigated the role of HOXA11-AS in driving GSC stemness properties via sphere-forming and protein chip assays.Results: Gain-of-function as well as loss-of-function results showed that the HOXA11-AS maybe a critical modulator in GBM recurrence as demonstrated by cell sphere-forming ability. Furthermore, we showed that induced expression of HOXA11-AS does increase the levels of stemness-related transcription factors (Oct4/Sox17/Sox2) in U87MG cells. In vivo xenograft experiments using the HOXA11-AS knockdown U87MG cells revealed that downregulation of HOXA11-AS could strongly inhibit tumor growth. Furthermore, we found that HOXA11-AS knockdown decreased the expression of cancer stemness markers in vivo.Conclusions: Collectively, these data suggests that HOXA11-AS is involved in GSC stemness and supports its clinical significance as a important therapeutic target in glioma.

Development of glioblastoma organoids and their applications in personalized therapy

Glioblastomas(GBMs)are the brain tumors with the highest malignancy and poorest prognoses.GBM is characterized by high heterogeneity and resistance to drug treatment.Organoids are 3-dimensional cultures that are constructed in vitro and comprise cell types highly similar to those in organs or tissues in vivo,thus simulating specific structures and physiological functions of organs.Organoids have been technically developed into an advanced ex vivo disease model used in basic and preclinical research on tumors.Brain organoids,which simulate the brain microenvironment while preserving tumor heterogeneity,have been used to predict patients’therapeutic responses to antitumor drugs,thus enabling a breakthrough in glioma research.GBM organoids provide an effective supplementary model that reflects human tumors’biological characteristics and functions in vitro more directly and accurately than traditional experimental models.Therefore,GBM organoids are widely applicable in disease mechanism research,drug development and screening,and glioma precision treatments.This review focuses on the development of various GBM organoid models and their applications in identifying new individualized therapies against drug-resistant GBM.

Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions

Precise tuning of gene expression,accomplished by regulato ry networks of transcription factors,epigenetic modifiers,and microRNAs,is crucial for the proper neural development and function of the brain cells.The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis,such as maintaining the cell stemness,cell prolife ration,cell fate decisions,and terminal diffe rentiation into neurons and glial cells.MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression.Together with other gene regulatory factors,microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment.The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain.Deregulated SOX/mic roRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies,including neurodegenerative disorders,traumatic brain injury,and cancer.Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neuro restoration.N umerous studies have confirmed complex intera ctions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma.Keeping in mind the crucial roles of SOX genes and microRNAs in neural development,we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions.Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies.

Interferon-beta inhibits human glioma stem cell growth by modulating immune response and cell cycle related signaling pathways

Malignant Glioma is characterized by strong self-renewal potential and immature differentiation potential.The main reason is that malignant glioma holds key cluster cells,glioma stem cells(GSCs).GSCs contribute to tumorigenesis,tumor progression,recurrence,and treatment resistance.Interferon-beta(IFN-β)is well known for its anti-proliferative efficacy in diverse cancers.IFN-βalso displayed potent antitumor effects in malignant glioma.IFN-βaffect both GSCs and Neural stem cells(NSCs)in the treatment of gliomas.However,the functional comparison,similar or different effects of IFN-βon GSCs and NSCs are rarely reported.Here,we studied the similarities and differences of the responses to IFN-βbetween human GSCs and normal NSCs.We found that IFN-βpreferentially inhibited GSCs over NSCs.The cell body and nucleus size of GSCs increased after IFN-βtreatment,and the genomic analysis revealed the enrichment of the upregulated immune response,cell adhesion genes and down regulated cell cycle,ribosome pathways.Several typical cyclin genes,including cyclin A2(CCNA2),cyclin B1(CCNB1),cyclin B2(CCNB2),and cyclin D1(CCND1),were significantly downregulated in GSCs after IFN-βstimulation.We also found that continuous IFN-βstimulation after passage further enhanced the inhibitory effect.Our study revealed how genetic diversity resulted in differential effects in response to IFN-βtreatment.These results may contribute to improve the applications of IFN-βin anti-cancer immunotherapy.In addition,these results may also help to design more effective pharmacological strategies to target cancer stem cells while protecting normal neural stem cells.

Comparative study on the stem cell phenotypes of C6 cells under different culture conditions

Background Glioma stem cell （GSC） hypothesis posits that a subpopulation of cells within gliomas have true clonogenic and tumorigenic potential. Significantly, a more controversial correlate to GSC is that cells in different culture conditions might display distinct stem cell properties. Considering these possibilities, we applied an approach comparing stem cell characteristics of C6 glioma cells under different culture conditions.Methods C6 cells were cultured under three different growth conditions, i.e., adherent growth in conventional 10% serum medium, non-adherent spheres growth in serum-free medium, as well as adherent growth on laminin-coated flask in serum-free medium. Growth characteristics were detected contrastively through neurosphere formation assay and cell cycle analysis. Markers were determined by immunofluorescence, relative-quantitative reverse transcription （RT）-PCR,Western blotting and flow cytometry. Side population cells were analyzed via flow cytometry. Tumor models were detected by magnetic resonance imaging and hematoxylin ＆ eosin staining. Data analyses were performed with SPSS software （17.0）.Results C6 cells （C6-Adh, C6-SC-Sph and C6-SC-Adh） showed distinctive growth patterns and proliferation capacity.Compared to suspending C6-SC-Sph, adherent C6-Adh and C6-SC-Adh displayed higher growth ratio. C6-SC-Sph and C6-SC-Adh showed enhanced capability of neurosphere formation and self-renewal. High side population ratio was detected in C6-SC-Sph and C6-SC-Adh. CD133 was not detected in all three kinds of cells. Conversely, Nestin and β-Ⅲ-tubulin were demonstrated positive, nonetheless with no statistical significance （P 〉0.05）. Interestingly, lower expression of glial fibrillary acidic protein was demonstrated in C6-SC-Sph and C6-SC-Adh. C6-Adh, C6-SC-Sph and C6-SC-Adh were all displayed in situ oncogenicity, while statistical difference of survival time was not confirmed.Conclusions C6 glioma cell line is endowed with some GSC phenotypes that can be moderately enriched in vitro when transferred into stem cell culture condition. The resultant tumor-spheres may be not a prerequisite or sound source of GSCs and adherent culture in stem cell medium is not a growth condition in favor of GSCs expanding in vivo.

Challenges of further studies on gliomas

Gliomas, particularly glioblastomas （GBMs）, are the most common and highly aggressive primary braintumors with poor prognosi-s, in {he past decade, a great many advances have been made in the study on cellular and molecular basis of gliomas. Numerous publications have explored the cell of origin of gliomas, the molecular genetic and epigenetic aberration in gliomas, the molecular classification of GBM subtypes, the possible oncometabolites, the application of targeted therapy for malignant gliomas, etc. However, considering all these findings in recent years, it is clear that a picture of the changes in gliomas is more complex and that it should be characterized further to gain a comprehensive and in-depth understanding of gliomagenesis and for translational application of the new insights into clinical practice, especially in the following important aspects.

Cross-talk between microRNAs,long non-coding RNAs and p21^(Cip1)in glioma:diagnostic,prognostic and therapeutic roles

Glioblastoma multiforme is considered one of the most common malignant primary intracranial tumors.Despite treatment with a combination of surgery,chemotherapy and radiotherapy,patients with glioblastoma multiform have poor prognosis.It has been widely accepted that the occurrence,progression,and even recurrence of glioblastoma multiforme strictly depends on the presence of glioma cancer stem cells.The presence of glioma stem cells reduces the efficacy of standard therapies,thus increasing the imperative to identify new targets and therapeutic strategies in glioblastoma patients.In this regard,the p21^(Cip1)pathway has been found to play an important role in the maintenance of the glioma stem cells.It has been shown that this pathway regulates cancer stem cell pool by preventing hyperproliferation and exhaustion.MicroRNAs,endogenous small non-coding RNAs,and long non-coding RNAs,regulate post-transcription gene expression.These are not only altered in glioma,but also in other cancer types,and are involved in tumor development and progression.Notably,they have also been shown to modulate the expression of proteins in the p21^(Cip1)signaling pathway.This review highlights the extent and complexity of cross-talk between microRNAs,long non-coding RNAs and the p21^(Cip1)pathway,and demonstrates how such interplay orchestrates the regulation of protein expression and functions in glioma and glioma stem cells.

Crosstalk of the Wnt/b-catenin pathway with other pathways in cancer cells

Many cancers have similar aberrations in various signaling cascades with crucial roles in cellular proliferation,differentiation,and morphogenesis.Dysregulation of signal cascades that play integral roles during early cellular development is well known to be a central feature of many malignancies.One such signaling cascade is the Wnt/b-catenin pathway,which has a profound effect on stem cell proliferation,migration,and differentiation.This pathway is dysregulated in numerous cell types,underscoring its global oncogenetic potential.This review highlights regulators and downstream effectors of this receptor cascade and addresses the increasingly apparent crosstalk of Wnt with other tumorigenic signaling pathways.As understanding of the genetic and epigenetic changes unique to these malignancies increases,identifying the regulatory mechanisms unique to the Wnt/b-catenin pathway and similarly aberrant receptor pathways will be imperative.