A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells

Manoranjan, Branavan; Chokshi, Chirayu; Venugopal, Chitra; Subapanditha, Minomi; Savage, Neil; Tatari, Nazanin; Provias, John; Murty, Naresh K.; Moffat, Jason; Doble, Bradley W.; Singh, Sheila K.

doi:10.1038/s41388-019-1086-x

Cited by 34 publications

(21 citation statements)

References 39 publications

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“…Several signaling pathways upregulated in GBM are involved in cell survival, growth and invasiveness that sustain tumor development and confer resistance to therapy and to harsh microenvironments (20). Among these pathways, current literature suggests that aberrant activation of the Wingless (WNT) signaling contributes to GBM pathology through different cell processes, such as proliferation (21,22), motility (23)(24)(25), cell fate specification (26), and maintenance of stemness properties (27,28). Interestingly, WNT signaling pathway emerged as a pivotal player to mediate the crosstalk between autophagy and EMT, regulating molecules and connecting to other important signal transduction cascades, such as the mTOR signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

et al. 2020

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Section: Introductionmentioning

confidence: 99%

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

et al. 2020

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“…The active CD133 primarily regulate WNT/β-catenin pathway to drive self-renewal. (Manoranjan et al, 2020). CD133 can regulate WNT signaling by another mode, where it forms a ternary complex with HDAC6 and β-catenin, stabilizing β-catenin, resulting in the activation of WNT/β-catenin signaling (Figure 3).…”

Section: Cd133mentioning

confidence: 99%

“…However, its relevance in stem cell biology was not unraveled until a physical interaction of CD133 to p85 subunit of PI3K was shown to activate its catalytic subunit p110 ( Wei et al, 2013 ). Further, the CD133/PI3K/AKT pathway is shown to activate WNT signaling to drive glioblastoma tumor-initiating cells ( Manoranjan et al, 2020 ). CD133 can regulate WNT signaling by another mode, where it forms a ternary complex with HDAC6 and β-catenin, stabilizing β-catenin, resulting in the activation of WNT/β-catenin signaling ( Figure 3 ).…”

Section: Markers Of Cscsmentioning

confidence: 99%

Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells

Mohan

Rajan

Mohan

et al. 2021

Front. Cell Dev. Biol.

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A subpopulation within cancer, known as cancer stem cells (CSCs), regulates tumor initiation, chemoresistance, and metastasis. At a closer look, CSCs show functional heterogeneity and hierarchical organization. The present review is an attempt to assign marker profiles to define the functional heterogeneity and hierarchical organization of CSCs, based on a series of single-cell analyses. The evidences show that analogous to stem cell hierarchy, self-renewing Quiescent CSCs give rise to the Progenitor CSCs with limited proliferative capacity, and later to a Progenitor-like CSCs, which differentiates to Proliferating non-CSCs. Functionally, the CSCs can be tumor-initiating cells (TICs), drug-resistant CSCs, or metastasis initiating cells (MICs). Although there are certain marker profiles used to identify CSCs of different cancers, molecules like CD44, CD133, ALDH1A1, ABCG2, and pluripotency markers [Octamer binding transcriptional factor 4 (OCT4), SOX2, and NANOG] are used to mark CSCs of a wide range of cancers, ranging from hematological malignancies to solid tumors. Our analysis of the recent reports showed that a combination of these markers can demarcate the heterogeneous CSCs in solid tumors. Reporter constructs are widely used for easy identification and quantification of marker molecules. In this review, we discuss the suitability of reporters for the widely used CSC markers that can define the heterogeneous CSCs. Since the CSC-specific functions of CD44 and CD133 are regulated at the post-translational level, we do not recommend the reporters for these molecules for the detection of CSCs. A promoter-based reporter for ABCG2 may also be not relevant in CSCs, as the expression of the molecule in cancer is mainly regulated by promoter demethylation. In this context, a dual reporter consisting of one of the pluripotency markers and ALDH1A1 will be useful in marking the heterogeneous CSCs. This system can be easily adapted to high-throughput platforms to screen drugs for eliminating CSCs.

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“…Additionally, the results of the study have indicated that CD133 may conceivably activate Wnt/β-catenin signaling pathway through AKT and leads to promote brain tumor-initiating cells in GBM. In other words, the outcome has shown that the CD133-AKT- Wnt/β-catenin axis drives glioblastoma-initiating cell tumor ( 4 ). The level of phosphorylate-Akt in CD133 Pos cancer cells is greater than in CD133 Neg cancer cells, notably in GSCs ( 5 ).…”

Section: The Signaling Crosstalk Between Cd133 Wnt/β-catenin and Tementioning

confidence: 99%

“…CD133, also known as prominin-1, has been used as an essential marker for the detection of GSCs. Additionally, CD133 has been shown to be associated with GBM development, recurrence, and poor overall survival ( 4 ). Emerging observations have suggested that CD133 could act as a novel receptor for PI3K/AKT/mTOR pathway ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Could We Address the Interplay Between CD133, Wnt/β-Catenin, and TERT Signaling Pathways as a Potential Target for Glioblastoma Therapy?

Behrooz

Syahir

2021

Front. Oncol.

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Glioblastoma multiforme (GBM) is one of the most lethal forms of primary brain tumors. Glioblastoma stem cells (GSCs) play an undeniable role in tumor development by activating multiple signaling pathways such as Wnt/β-catenin and PI3K/AKT/mTOR that facilitate brain tumor formation. CD133, a transmembrane glycoprotein, has been used to classify cancer stem cells (CSCs) in GBM. The therapeutic value of CD133 is a biomarker of the CSC in multiple cancers. It also leads to growth and recurrence of the tumor. More recent findings have confirmed the association of telomerase/TERT with Wnt/β-catenin and the PI3K/AKT/mTOR signaling pathways. Advance studies have shown that crosstalk between CD133, Wnt/β-catenin, and telomerase/TERT can facilitate GBM stemness and lead to therapeutic resistance. Mechanistic insight into signaling mechanisms downstream of surface biomarkers has been revolutionized by facilitating targeting of tumor-specific molecular deregulation. This review also addresses the importance of interplay between CD133, Wnt/β-catenin and TERT signaling pathways in GSCs and outlines the future therapeutic goals for glioblastoma treatment.

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A CD133-AKT-Wnt signaling axis drives glioblastoma brain tumor-initiating cells

Cited by 34 publications

References 39 publications

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

Markers and Reporters to Reveal the Hierarchy in Heterogeneous Cancer Stem Cells

Could We Address the Interplay Between CD133, Wnt/β-Catenin, and TERT Signaling Pathways as a Potential Target for Glioblastoma Therapy?

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