Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression - PubMed (original) (raw)

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Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression

Christian T Meisel et al. Cells. 2020.

Abstract

The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.

Keywords: Notch signaling pathway; cancer; cancer diagnosis; cancer stem cells; cancer therapy; chemoresistance; metastasis; radioresistance; stem cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

Differential regulation of Notch activity in various types of cancer. Depending on the cancer type, the Notch pathway can be hyper- or hypo-activated. Specific Notch receptors are involved in this differential regulation. Hyperactivation of the pathway through specific receptors is indicated in green. Repression of Notch activity is indicated in red. In some organs, both activation and repression of the pathway have been reported, depending on the subtype of tumors or the model system analyzed.

Figure 2

Figure 2

The Notch signaling pathway in cancerogenic events. The Notch pathway is implicated in a variety of tumorigenic processes. Specific receptors have been reported to facilitate tumorigenic events such as epithelial to mesenchymal transition (EMT), angiogenesis, maintenance of a hypoxic environment, proliferation, cancer stem cell self-renewal and immunomodulation.

Figure 3

Figure 3

Targeting the Notch pathway in tumorigenesis. Several therapeutic approaches against cancer target the Notch pathway at different levels. Gamma secretase blockers are inhibiting the process of S3 cleavage of the Notch intracellular domain (NICD), thereby blocking downstream gene transcription. Agents blocking receptor–ligand interaction, namely antibody OMP21M18 binds the Notch extracellular domain (NECD), thereby preventing proteolytic cleavage. While MEDI0639 inhibits the direct interaction of ligand and receptor. The decoy N1110-24 blocks JAG1/JAG2 mediated Notch1 signaling, while N11-13 blocks DLL1-DLL4-mediated NOTCH1 signaling. The blocker of transcription IMR-1, disrupts the recruitment of Mastermind-like1 to the Notch activation complex on chromatin. Whereas the mastermind-like proteins (MALM) peptide competes with endogenous MAML in the cell, reducing the affinity of the endogenous MAML binding to NICD and CSL in the transcription complex.

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