Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt-Beta-Catenin Pathways in CD44+ Gastric Cancer Stem Cells

Barat, Samarpita; Chen, Xi; Bui, Khac Cuong; Bożko, Przemysław; Götze, Julian; Christgen, Matthias; Krech, Till; Malek, Nisar P.; Plentz, Ruben R.

doi:10.1002/sctm.16-0335

Cited by 31 publications

(29 citation statements)

References 44 publications

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“…Our study also revealed that PS1 plays an important role in CD44s-mediated EMT induction. Therefore, in addition to confirming previous studies showing that gamma-secretase inhibitors are effective in inhibiting CSC properties via suppression of Notch activity [ 28 , 29 ], the present results point to the existence of another mechanism mediating the suppressive effects of gamma-secretase on CSCs. Combination treatment using CDDP and gamma-secretase inhibitors might be a useful approach in overcoming the resistance of several types of cancers to chemotherapy.…”

Section: Discussionsupporting

confidence: 90%

CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells

Mitsuya

Takahashi²,

Prieto‐Vila³

et al. 2018

Oncotarget

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A number of studies report that epithelial to mesenchymal transition (EMT) supports the generation and maintenance of cancer stem cells (CSCs), which show tumor seeding ability and drug resistance; however, the molecular mechanisms underlying induction of EMT-associated tumor malignancy remain unclear. The present study reports that oral cancer cells switch from expressing the CD44 variant form (CD44v) to expressing the standard form (CD44s) during acquisition of cisplatin-resistance, which resulted in EMT induction. CD44s induced an EMT phenotype in cisplatin resistant cells by up-regulating ZEB1, a transcriptional repressor of E-cadherin. More importantly, CD44s up-regulated ZEB1 by suppressing microRNA-200c, which is a non-coding RNA that directly represses the ZEB1 gene. These results demonstrate the importance of the association between platinum resistance and CD44s during EMT induction in oral cancer cells.

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Section: Discussionsupporting

confidence: 90%

CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells

Mitsuya

Takahashi²,

Prieto‐Vila³

et al. 2018

Oncotarget

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“…Previous studies have reported CSCs to be involved in the stepwise progression of solid tumors including breast, gastric, and cervical cancer . CD44 and activation of WNT, NOTCH1 increases aggressiveness, correlating with progression in colon cancer . CD133 is also associated with enrichment of undifferentiated cells and tumorigenic behavior along with its implication in epithelial dedifferentiation .…”

Section: Discussionmentioning

confidence: 99%

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Kulsum

Raju²,

Raghavan³

et al. 2019

Molecular Carcinogenesis

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Understanding the cellular interactions during oral carcinogenesis has the potential to identify novel prognostic and therapeutic targets. This study aimed at investigating the cancer stem cell (CSC)‐fibroblast niche interactions using in‐vitro dysplastic cell line models developed from different stages of 4NQO‐induced oral carcinogenic mice model. The spontaneously transformed epithelial cells (DysMSCTR6, 14 and 16) were developed from three time points (mild/moderate/severe), while two fibroblast cell lines (FibroMSCTR12, 16) were developed from moderate and severe dysplastic tissue. The epithelial (Epcam+/Ck+) and the fibroblast cell lines (Vimentin+/α‐SMA+/Ck‐) were authenticated and assessment of cells representing progressive grades of dysplastic severity indicated a significant increase in dysplastic marker profile (P < 0.05). Evaluation of the CSC characteristics showed that an increase in expression of Cd133, Cd44, Aldh1a1, Notch1, and Sox2 was accompanied by an increase in migratory (P > 0.05) and colony formation capacity (P > 0.005). Targeting Notch1 (GSI inhibitor PZ0187; 30 μM), showed a significant reduction in cell proliferation capacity (P < 0.05) and in the dysplastic marker profile. Further, Notch1 inhibition resulted in down regulation of Cd133 and Aldh1a 1 (P < 0.05) and a complete abrogation of colony formation ability (P < 0.0001). The effect of niche interactions evaluated using FibroMSCTR12‐conditioned media studies, revealed an enrichment of ALDH1A1+ cells (P < 0.05), induction of spheroid formation ability (P < 0.0001) and increased proliferation capacity (3.7 fold; P < 0.005). Although PZ0187 reduced cell viability by ∼40%, was unable to abrogate the conditioned‐media induced increase in proliferation capacity completely. This study reports a Notch‐1 dependent enrichment of CSC properties during dysplastic progression and a Notch‐1 independent dysplastic cell‐fibroblast interaction during oral carcinogenesis.

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“…Blockade of Notch receptors using Numb, an endogenous inhibitor of Notch receptors in CD133 + CD24 + renal cell carcinoma CSCs, led to a reduction in self-renewal and drug resistance in these CSCs [136]. Treatment with gamma-secretase inhibitor IX (GSI), a Notch inhibitor, inhibited proliferation and induced apoptosis in CD44 + gastric CSCs [137]. These studies collectively suggest the importance of Notch signaling in the maintenance of stemness in CSCs.…”

Section: Maintenance Of “Cancer Stemness”mentioning

confidence: 99%

Unraveling the journey of cancer stem cells from origin to metastasis

Nimmakayala

Batra

Ponnusamy

2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Cancer biology research over recent decades has given ample evidence for the existence of self-renewing and drug-resistant populations within heterogeneous tumors, widely recognized as cancer stem cells (CSCs). However, a lack of clear understanding about the origin, existence, maintenance, and metastatic roles of CSCs limit efforts towards the development of CSC-targeted therapy. In this review, we describe novel avenues of current CSC biology. In addition to cell fusion and horizontal gene transfer, CSCs are originated by mutations in somatic or differentiated cancer cells, resulting in de-differentiation and reprogramming. Recent studies also provided evidence for the existence of distinct or heterogeneous CSC populations within a single heterogeneous tumor. Our analysis of the literature also opens the doors for a novel hypothesis that CSC populations with specific phenotypes, metabolic profiles, and clonogenic potential metastasize to specific organs.

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Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt-Beta-Catenin Pathways in CD44+ Gastric Cancer Stem Cells

Cited by 31 publications

References 44 publications

CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells

CD44 exerts a functional role during EMT induction in cisplatin-resistant head and neck cancer cells

Cancer stem cells and fibroblast niche cross talk in an in‐vitro oral dysplasia model

Unraveling the journey of cancer stem cells from origin to metastasis

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