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  • br Notch Similar to the Wnt and Hedgehog

    2021-10-13


    Notch Similar to the Wnt and Hedgehog pathways as discussed earlier, Notch is an evolutionarily conserved primordial developmental pathway which affects patterning, and has an important role to play in cancer biology ranging from angiogenesis to cancer stem faah inhibitor to tumor immunity [88]. Notch signaling occurs in cells which are in contact, with one cell displaying the transmembrane Notch-specific ligand (Delta-like ligands and Jagged) on its surface while the other cell displaying the transmembrane Notch receptor [89]. This interaction is mediated by two subsequent cleavage events of the Notch receptor upon ligand contact, both mediated by important protease enzymes. The first cleavage is mediated by the ADAM (a disintegrin and metalloproteinase) enzymes, either ADAM 10 or ADAM 17 (also called TACE - tumour necrosis factor-α converting enzyme), thus cleaving off the Notch extracellular domain (NECD); while the second cleavage event is mediated by γ-secretase which cleaves and releases the Notch intracellular domain (NICD), which then directly translocates into the nucleus to activate Notch-target genes transcription (Fig. 4). Interestingly, the Notch precursor protein undergoes a preliminary cleavage by a furin-like convertase to get converted into the active and functional form, before it is trafficked to the plasma membrane for participating in signal reception. There are canonical and non-canonical pathways in the Notch signaling cascade as well. There are five canonical Notch ligands that have been characterized – the Delta-like ligands 1, 2, 3 and 4 (DLL1, DLL2, DLL3 and DLL4), and Jagged1 and Jagged2. Besides, there are four Notch receptor paralogues characterized as of yet – Notch1, Notch2, Notch3 and Notch4 [90]. Evidently, the Notch pathway is complex and multifunctional – different cells can express different Notch receptors and ligands. Notch non-canonical pathways have begun to be unveiled [91] recently, and some might also have relevance in cancer development and maintenance. The NICD translocates to the nucleus to bind to the constitutive transcriptional repressor CSL (CBF-1-Suppressor of Hairless/Lag1, also known as RBP-jκ), thus displacing co-repressors and recruiting co-activators like the MAML (Mastermind-like proteins, homologous to Drosophila Mastermind). Following the formation of the Notch–CSL–MAML complex, multiple transcriptional regulators that form the NTC, or the Notch transcriptional complex are recruited [92,93]. Notch triggers genes that are associated with differentiation and/or survival, including cyclin D1 [94] and the proto-oncogene c-Myc [95]. The Notch paralog, ligand, and cell type might determine which genomic sites the Notch signaling cascade activates transcription of.
    Crosstalks among the developmental pathways
    Conclusion
    Future perspectives With the gradual elucidation of roles played by the different developmental pathways in oncogenesis and maintenance of cancer stem cell population along with tumor relapse, numerous molecules have been tested as drug candidates, each targeting major mediators of the cascades. Some well-known ones are γ-secretase inhibitors (eg. RO4929097) and anti-DLL monoclonal antibodies (eg. enoticumab) which target the Notch pathway, SMO inhibitors (eg. Vismodegib, bevacizumab) that target the Hedgehog pathway and agents inhibiting the activities of Dishevelled (eg. sulindac) and β-catenin (eg. celecoxib), as well anti-Frizzled (eg. Vantictumab, OMP‑54F28) antibodies which are targeted against the Wnt pathway [162]. Most of them have been successful, however, in many cases, stem cell populations have survived or tumor relapse had occurred, and sometimes, administration of these drugs in combination with other drugs in clinical trials showed no better results [163], i.e., speculation arose that either they did not have any synergistic or additive effect, or the transformed cells had become resistant to the pathway inhibitors – the latter being established today. The aim of combination therapies is to potentially reduce drug resistance besides providing optimal therapeutic anti-cancer benefits. It increases the efficacy of the treatment compared to the mono-therapy strategies by targeting key pathways simultaneously, to provide synergistic or additive benefits [20].