Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition

Espinoza, Ingrid; Pochampally, Radhika; Xing, Fei; Watabe, Kounosuke; Miele, Lucio

doi:10.2147/ott.s36162

Cited by 106 publications

(76 citation statements)

References 147 publications

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“…Colon CSCs show a high level of WNT signalling, with nuclear β-catenin at the invasive cancer front and in scattered tumour cells 240,241 . Notch signalling contributes to the generation of CSCs in other cancers 242 , including pancreatic adenocarcinomas 243 , and the inhibition of Notch signalling suppresses EMT and CSCs in a xenograft model 244 . As is the case in EMT- and MET-based cell reprogramming, miRNAs contribute to the generation and maintenance of CSCs.…”

Section: Figurementioning

confidence: 99%

Molecular mechanisms of epithelial–mesenchymal transition

Lamouille

Derynck

2014

Nat Rev Mol Cell Biol

6,589

151

6,700

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The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial–mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

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Section: Figurementioning

confidence: 99%

Molecular mechanisms of epithelial–mesenchymal transition

Lamouille

Derynck

2014

Nat Rev Mol Cell Biol

6,589

151

6,700

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“…Notch signalling can interface with and influence a large number of cancer-relevant pathways—controlling EMT, DNA repair, the cell cycle, and apoptosis. 2,72 For example, cooperation between β-catenin (Wnt) and Notch signalling has been documented in colorectal cancer 73,74 and myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML); 75 Notch and transforming growth factor-β (TGF-β) are known to have cooperative tumorigenic effects in RCC 76 and TNBC. 77 As described, Notch-signalling inhibitors, similar to inhibitors that target other developmental pathways relevant to CSCs, will not necessarily produce singleagent, short-term tumour volume responses in early phase clinical trials, unless they have considerable cytostatic, cytotoxic or antiangiogenic activity separate from their effect on CSCs.…”

Section: Targeting the Notch Pathwaymentioning

confidence: 99%

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

et al. 2015

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During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

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“…Activating and inactivating mutations in Notch result in a variety of hematopoietic and solid tumors, indicating that Notch can function as a tumor suppressor or tumor promoter depending on context [7]. As a result, Notch signaling has emerged as molecular target of a variety of cancers [6,8,9,10]. Thus, a thorough understanding of this pathway and how it is regulated will contribute to advancement of basic biology as well as medical science.…”

Section: Introductionmentioning

confidence: 99%

Significance of glycosylation in Notch signaling

Takeuchi

Haltiwanger

2014

Biochemical and Biophysical Research Communications

143

127

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Notch signaling is essential for cell-fate specification in metazoans, and dysregulation of the pathway leads to a variety of human diseases including heart and vascular defects as well as cancer. Glycosylation of the Notch extracellular domain has emerged as an elegant means for regulating Notch activity, especially since the discovery that Fringe is a glycosyltransferase that modifies O-fucose in 2000. Since then, several other O-glycans on the extracellular domain have been demonstrated to modulate Notch activity. Here we will describe recent results on the molecular mechanisms by which Fringe modulates Notch activity, summarize recent work on how O-glucose, O-GlcNAc, and O-GalNAc glycans affect Notch, and discuss several human genetic disorders resulting from defects in Notch glycosylation.

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Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition

Cited by 106 publications

References 147 publications

Molecular mechanisms of epithelial–mesenchymal transition

Molecular mechanisms of epithelial–mesenchymal transition

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Significance of glycosylation in Notch signaling

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