Aberrant Notch signaling in glioblastoma stem cells contributes to tumor recurrence and invasion

Yu, Jin; Jiang, Hao; Zhan, Renya

doi:10.3892/mmr.2016.5391

Cited by 34 publications

(31 citation statements)

References 23 publications

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“…PDGFR and NOTCH1 are highly enriched in GBM, and targeting these two genes to treat GBM is currently under investigation [24–37]. By using the GlioVis program, we analyzed the mRNA levels of NOTCH1 gene and PDGFR isoforms (PDGFRA and PDGFRB) in more than 500 GBM patients from The Cancer Genome Atlas (TCGA) database.…”

Section: Resultsmentioning

confidence: 99%

“…Among these therapeutic targets, NOTCH1 [24–31] and PDGFR [32–37] (platelet-derived growth factor receptors) have received more attention recently given their important roles in GSCs. Our previous research demonstrates that NOTCH1-positive GSCs are more potent to self renew than NOTCH1-negative cells, suggesting that NOTCH1-positive GSCs are more tumorigenic [31].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous research demonstrates that NOTCH1-positive GSCs are more potent to self renew than NOTCH1-negative cells, suggesting that NOTCH1-positive GSCs are more tumorigenic [31]. Blocking NOTCH1 has been applied to GSCs and this treatment has received promising therapeutic efficacy in vitro [24, 29, 30]. GSCs also highly express PDGFR, and targeting this gene using a multikinase inhibitor, imatinib, effectively kills GSCs [33, 36, 38–40].…”

Section: Introductionmentioning

confidence: 99%

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Patient-derived glioblastoma stem cells respond differentially to targeted therapies

et al. 2016

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The dismal prognosis of glioblastoma is, at least in part, attributable to the difficulty in eradicating glioblastoma stem cells (GSCs). However, whether this difficulty is caused by the differential responses of GSCs to drugs remains to be determined. To address this, we isolated and characterized ten GSC lines from established cell lines, xenografts, or patient specimens. Six lines formed spheres in a regular culture condition, whereas the remaining four lines grew as monolayer. These adherent lines formed spheres only in plates coated with poly-2-hydroxyethyl methacrylate. The self-renewal capabilities of GSCs varied, with the cell density needed for sphere formation ranging from 4 to 23.8 cells/well. Moreover, a single non-adherent GSC either remained quiescent or divided into two cells in four-seven days. The stem cell identity of GSCs was further verified by the expression of nestin or glial fibrillary acidic protein. Of the two GSC lines that were injected in immunodeficient mice, only one line formed a tumor in two months. The protein levels of NOTCH1 and platelet derived growth factor receptor alpha positively correlated with the responsiveness of GSCs to γ-secretase inhibitor IX or imatinib, two compounds that inhibit these two proteins, respectively. Furthermore, a combination of temozolomide and a connexin 43 inhibitor robustly inhibited the growth of GSCs. Collectively, our results demonstrate that patient-derived GSCs exhibit different growth rates in culture, possess differential capabilities to form a tumor, and have varied responses to targeted therapies. Our findings underscore the importance of patient-derived GSCs in glioblastoma research and therapeutic development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Patient-derived glioblastoma stem cells respond differentially to targeted therapies

et al. 2016

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“…In the case of solid tumours, expression of embryonic stem cell markers such as Oct4 and Sox2 is commonly seen in association with aberrant Notch expression [44] , it and may promote metastasis by modulating epithelialto-mesenchymal transition programmes, a process also known to involve Hedgehog signalling. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.…”

Section: Resultsmentioning

confidence: 99%

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Dempke¹,

Fenchel

Uciechowski

et al. 2017

Oncology

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Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.

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“…Although the role of stem-like cells has been extensively evaluated, their contribution to relapse, chemo- and radio-therapy resistance [2] and the role of vascular cells such as microglia, peripheral immune and neural processor cells; in the generation of a specific niche within which GBM cells can evade immune detection is a topic of ongoing research. A detailed understanding of the supportive role that the microenvironment plays in GBM is critical to the design of effective immunotherapeutic strategies.…”

Section: Tumour Microenvironmentmentioning

confidence: 99%

Advances in immunotherapy for the treatment of glioblastoma

et al. 2016

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Glioblastoma (GBM) is an aggressive brain tumour, associated with extremely poor prognosis and although there have been therapeutic advances, treatment options remain limited. This review focuses on the use of immunotherapy, harnessing the power of the host’s immune system to reject cancer cells. Key challenges in glioma specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumour. Although specific antigens have been identified in several cancers; brain tumours, such as GBM, are considered poorly immunogenic. However, as detailed in this review, strategies aimed at circumventing these challenges are showing promise for GBM treatment; including identification of glioma specific antigens and endogenous immune cell activation in an attempt to overcome the immunosuppressive environment which is associated with GBM tumours. An up-to-date summary of current Phase I/II and ongoing Phase III GBM immunotherapy clinical trials is provided in addition to insights into promising preclinical approaches which are focused predominantly on increased induction of Type 1 helper T cell (Th1) immune responses within patients.

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Aberrant Notch signaling in glioblastoma stem cells contributes to tumor recurrence and invasion

Cited by 34 publications

References 23 publications

Patient-derived glioblastoma stem cells respond differentially to targeted therapies

Patient-derived glioblastoma stem cells respond differentially to targeted therapies

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Advances in immunotherapy for the treatment of glioblastoma

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