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The Roles of Notch Signaling in Cancers
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The Roles of Notch Signaling in Cancers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 61233

Special Issue Editor

Dr. Catia Giovannini

E-Mail Website
Guest Editor
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
Interests: cancer therapy; HCC; immunotherapy; notch signaling; flow cytometry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Notch signaling pathway is a conserved system involved in embryonic cell fate decisions and in the maintenance of adult stem cells through cell to cell communication. Many studies have shown the relevance of Notch signaling in different human diseases and in particular in cancer, where it is emerging as a major player. Indeed, dysregulation of Notch signaling has been found in a variety of human malignancies, where it is involved in either survival or death pathways, growth arrest, or proliferation and differentiation. The cellular outcome of this aberrant Notch signaling is highly dependent on the context and on the interactions with the tumor microenvironment; thus, it is not surprising that Notch receptors can act as an oncogene or tumor suppressor in different contexts. This Special Issue is aimed at summarizing the current knowledge on the role of Notch in cancer and possible therapeutic perspectives.

Dr. Catia Giovannini
Guest Editor

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Keywords

  • Notch
  • cancer
  • miRNAs

Published Papers (13 papers)

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Research

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18 pages, 5171 KiB  
Article
Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL
by Rainer Hubmann, Susanne Schnabl, Mohammad Araghi, Christian Schmidl, André F. Rendeiro, Martin Hilgarth, Dita Demirtas, Farghaly Ali, Philipp B. Staber, Peter Valent, Christoph Zielinski, Ulrich Jäger and Medhat Shehata
Cells 2020, 9(6), 1484; https://doi.org/10.3390/cells9061484 - 18 Jun 2020
Cited by 6 | Viewed by 3990
Abstract
NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). We compared the anti-neoplastic effects of the nuclear NOTCH2 inhibitor gliotoxin and the pan-NOTCH γ-secretase inhibitor RO4929097 in primary CLL cells with special emphasis on the individual roles of the different [...] Read more.
NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). We compared the anti-neoplastic effects of the nuclear NOTCH2 inhibitor gliotoxin and the pan-NOTCH γ-secretase inhibitor RO4929097 in primary CLL cells with special emphasis on the individual roles of the different NOTCH receptors. Gliotoxin rapidly induced apoptosis in all CLL cases tested, whereas RO4929097 exerted a variable and delayed effect on CLL cell viability. Gliotoxin-induced apoptosis was associated with inhibition of the NOTCH2/FCER2 (CD23) axis together with concomitant upregulation of the NOTCH3/NR4A1 axis. In contrast, RO4929097 downregulated the NOTCH3/NR4A1 axis and counteracted the spontaneous and gliotoxin-induced apoptosis. On the cell surface, NOTCH3 and CD23 expression were mutually exclusive, suggesting that downregulation of NOTCH2 signaling is a prerequisite for NOTCH3 expression in CLL cells. ATAC-seq confirmed that gliotoxin targeted the canonical NOTCH signaling, as indicated by the loss of chromatin accessibility at the potential NOTCH/CSL site containing the gene regulatory elements. This was accompanied by a gain in accessibility at the NR4A1, NFκB, and ATF3 motifs close to the genes involved in B-cell activation, differentiation, and apoptosis. In summary, these data show that gliotoxin recovers a non-canonical tumor-suppressing NOTCH3 activity, indicating that nuclear NOTCH2 inhibitors might be beneficial compared to pan-NOTCH inhibitors in the treatment of CLL. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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Review

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21 pages, 1489 KiB  
Review
Notch Signaling Regulation in HCC: From Hepatitis Virus to Non-Coding RNAs
by Catia Giovannini, Francesca Fornari, Fabio Piscaglia and Laura Gramantieri
Cells 2021, 10(3), 521; https://doi.org/10.3390/cells10030521 - 01 Mar 2021
Cited by 12 | Viewed by 2800
Abstract
The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles [...] Read more.
The Notch family includes evolutionary conserved genes that encode for single-pass transmembrane receptors involved in stem cell maintenance, development and cell fate determination of many cell lineages. Upon activation by different ligands, and depending on the cell type, Notch signaling plays pleomorphic roles in hepatocellular carcinoma (HCC) affecting neoplastic growth, invasion capability and stem like properties. A specific knowledge of the deregulated expression of each Notch receptor and ligand, coupled with resultant phenotypic changes, is still lacking in HCC. Therefore, while interfering with Notch signaling might represent a promising therapeutic approach, the complexity of Notch/ligands interactions and the variable consequences of their modulations raises concerns when performed in undefined molecular background. The gamma-secretase inhibitors (GSIs), representing the most utilized approach for Notch inhibition in clinical trials, are characterized by important adverse effects due to the non-specific nature of GSIs themselves and to the lack of molecular criteria guiding patient selection. In this review, we briefly summarize the mechanisms involved in Notch pathway activation in HCC supporting the development of alternatives to the γ-secretase pan-inhibitor for HCC therapy. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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32 pages, 3145 KiB  
Review
Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis
by Julia O. Misiorek, Alicja Przybyszewska-Podstawka, Joanna Kałafut, Beata Paziewska, Katarzyna Rolle, Adolfo Rivero-Müller and Matthias Nees
Cells 2021, 10(1), 94; https://doi.org/10.3390/cells10010094 - 07 Jan 2021
Cited by 44 | Viewed by 4343
Abstract
The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by [...] Read more.
The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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21 pages, 1504 KiB  
Review
Role of Notch Receptors in Hematologic Malignancies
by Laura Gragnani, Serena Lorini, Silvia Marri and Anna Linda Zignego
Cells 2021, 10(1), 16; https://doi.org/10.3390/cells10010016 - 24 Dec 2020
Cited by 10 | Viewed by 3459
Abstract
Notch receptors are single-pass transmembrane proteins that play a critical role in cell fate decisions and have been implicated in the regulation of many developmental processes. The human Notch family comprises of four receptors (Notch 1 to 4) and five ligands. Their signaling [...] Read more.
Notch receptors are single-pass transmembrane proteins that play a critical role in cell fate decisions and have been implicated in the regulation of many developmental processes. The human Notch family comprises of four receptors (Notch 1 to 4) and five ligands. Their signaling can regulate extremely basic cellular processes such as differentiation, proliferation and death. Notch is also involved in hematopoiesis and angiogenesis, and increasing evidence suggests that these genes are involved and frequently deregulated in several human malignancies, contributing to cell autonomous activities that may be either oncogenic or tumor suppressive. It was recently proposed that Notch signaling could play an active role in promoting and sustaining a broad spectrum of lymphoid malignancies as well as mutations in Notch family members that are present in several disorders of T- and B-cells, which could be responsible for altering the related signaling. Therefore, different Notch pathway molecules could be considered as potential therapeutic targets for hematological cancers. In this review, we will summarize and discuss compelling evidence pointing to Notch receptors as pleiotropic regulators of hematologic malignancies biology, first describing the physiological role of their signaling in T- and B-cell development and homeostasis, in order to fully understand the pathological alterations reported. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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30 pages, 2758 KiB  
Review
NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma
by Pooja A. Shah, Chenfei Huang, Qiuli Li, Sawad A. Kazi, Lauren A. Byers, Jing Wang, Faye M. Johnson and Mitchell J. Frederick
Cells 2020, 9(12), 2677; https://doi.org/10.3390/cells9122677 - 12 Dec 2020
Cited by 37 | Viewed by 4727
Abstract
Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated [...] Read more.
Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1’s role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer’s genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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18 pages, 1275 KiB  
Review
Notch Signaling Function in the Angiocrine Regulation of Tumor Development
by Alexandre Trindade and António Duarte
Cells 2020, 9(11), 2467; https://doi.org/10.3390/cells9112467 - 12 Nov 2020
Cited by 14 | Viewed by 3036
Abstract
The concept of tumor growth being angiogenesis dependent had its origin in the observations of Judah Folkman in 1969 of a retinoblastoma in a child. Tumor angiogenesis is initiated when endothelial cells (ECs) respond to local stimuli and migrate towards the growing mass, [...] Read more.
The concept of tumor growth being angiogenesis dependent had its origin in the observations of Judah Folkman in 1969 of a retinoblastoma in a child. Tumor angiogenesis is initiated when endothelial cells (ECs) respond to local stimuli and migrate towards the growing mass, which results in the formation of tubular structures surrounded by perivascular support cells that transport blood to the inner tumor. In turn, the neo-vasculature supports tumor development and eventual metastasis. This process is highly regulated by several signaling pathways. Central to this process is the Notch signaling pathway. Beyond the role of Notch signaling in tumor angiogenesis, a major hallmark of cancer development, it has also been implicated in the regulation of tumor cell proliferation and survival, in epithelial-to-mesenchymal transition, invasion and metastasis and in the regulation of cancer stem cells, in a variety of hematologic and solid malignancies. There is increasing evidence for the tumor vasculature being important in roles other than those linked to blood perfusion. Namely, endothelial cells act on and influence neighboring tumor cells by use of angiocrine factors to generate a unique cellular microenvironment, thereby regulating tumor stem-like cells’ homeostasis, modulating tumor progression, invasiveness, trafficking and metastasis. This review will focus on Notch signaling components that play a part in angiocrine signaling in a tumor setting. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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18 pages, 640 KiB  
Review
Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma
by Elena Parmigiani, Verdon Taylor and Claudio Giachino
Cells 2020, 9(10), 2304; https://doi.org/10.3390/cells9102304 - 15 Oct 2020
Cited by 42 | Viewed by 5498
Abstract
Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we [...] Read more.
Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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26 pages, 2927 KiB  
Review
Targeting Notch Trafficking and Processing in Cancers
by Luca Pagliaro, Claudia Sorrentino and Giovanni Roti
Cells 2020, 9(10), 2212; https://doi.org/10.3390/cells9102212 - 29 Sep 2020
Cited by 10 | Viewed by 3655
Abstract
The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory [...] Read more.
The Notch family comprises a group of four ligand-dependent receptors that control evolutionarily conserved developmental and homeostatic processes and transmit signals to the microenvironment. NOTCH undergoes remodeling, maturation, and trafficking in a series of post-translational events, including glycosylation, ubiquitination, and endocytosis. The regulatory modifications occurring in the endoplasmic reticulum/Golgi precede the intramembrane γ-secretase proteolysis and the transfer of active NOTCH to the nucleus. Hence, NOTCH proteins coexist in different subcellular compartments and undergo continuous relocation. Various factors, including ion concentration, enzymatic activity, and co-regulatory elements control Notch trafficking. Interfering with these regulatory mechanisms represents an innovative therapeutic way to bar oncogenic Notch signaling. In this review, we briefly summarize the role of Notch signaling in cancer and describe the protein modifications required for NOTCH to relocate across different subcellular compartments. We focus on the functional relationship between these modifications and the corresponding therapeutic options, and our findings could support the development of trafficking modulators as a potential alternative to the well-known γ-secretase inhibitors. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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19 pages, 3202 KiB  
Review
Notch Signaling in Breast Cancer: A Role in Drug Resistance
by McKenna BeLow and Clodia Osipo
Cells 2020, 9(10), 2204; https://doi.org/10.3390/cells9102204 - 29 Sep 2020
Cited by 52 | Viewed by 5641
Abstract
Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by [...] Read more.
Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate, including survival and self-renewal of stem cells, proliferation, or differentiation. Deregulation of Notch signaling promotes resistance to targeted or cytotoxic therapies by enriching of a small population of resistant cells, referred to as breast cancer stem cells, within the bulk tumor; enhancing stem-like features during the process of de-differentiation of tumor cells; or promoting epithelial to mesenchymal transition. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance through reduction or elimination of breast cancer stem cells. However, Notch inhibitors have yet to be clinically approved for the treatment of breast cancer, mainly due to dose-limiting gastrointestinal toxicity. In this review, we discuss potential mechanisms of Notch-mediated resistance in breast cancer cells and breast cancer stem cells, and various methods of targeting Notch through γ-secretase inhibitors, Notch signaling biologics, or transcriptional inhibitors. We also discuss future plans for identification of novel Notch-targeted therapies, in order to reduce toxicity and improve outcomes for women with resistant breast cancer. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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33 pages, 1290 KiB  
Review
Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression
by Christian T. Meisel, Cristina Porcheri and Thimios A. Mitsiadis
Cells 2020, 9(8), 1879; https://doi.org/10.3390/cells9081879 - 11 Aug 2020
Cited by 46 | Viewed by 5351
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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18 pages, 1455 KiB  
Review
Notch-Inflammation Networks in Regulation of Breast Cancer Progression
by Yulia Liubomirski and Adit Ben-Baruch
Cells 2020, 9(7), 1576; https://doi.org/10.3390/cells9071576 - 28 Jun 2020
Cited by 12 | Viewed by 3057
Abstract
Members of the Notch family and chronic inflammation were each separately demonstrated to have prominent malignancy-supporting roles in breast cancer. Recent investigations indicate that bi-directional interactions that exist between these two pathways promote the malignancy phenotype of breast tumor cells and of their [...] Read more.
Members of the Notch family and chronic inflammation were each separately demonstrated to have prominent malignancy-supporting roles in breast cancer. Recent investigations indicate that bi-directional interactions that exist between these two pathways promote the malignancy phenotype of breast tumor cells and of their tumor microenvironment. In this review article, we demonstrate the importance of Notch-inflammation interplays in malignancy by describing three key networks that act in breast cancer and their impacts on functions that contribute to disease progression: (1) Cross-talks of the Notch pathway with myeloid cells that are important players in cancer-related inflammation, focusing mainly on macrophages; (2) Cross-talks of the Notch pathway with pro-inflammatory factors, exemplified mainly by Notch interactions with interleukin 6 and its downstream pathways (STAT3); (3) Cross-talks of the Notch pathway with typical inflammatory transcription factors, primarily NF-κB. These three networks enhance tumor-promoting functions in different breast tumor subtypes and act in reciprocal manners, whereby Notch family members activate inflammatory elements and vice versa. These characteristics illustrate the fundamental roles played by Notch-inflammation interactions in elevating breast cancer progression and propose that joint targeting of both pathways together may provide more effective and less toxic treatment approaches in this disease. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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15 pages, 816 KiB  
Review
A Review on Notch Signaling and Colorectal Cancer
by Ashish Tyagi, Arun K. Sharma and Chendil Damodaran
Cells 2020, 9(6), 1549; https://doi.org/10.3390/cells9061549 - 25 Jun 2020
Cited by 86 | Viewed by 7071
Abstract
Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according [...] Read more.
Colorectal cancer (CRC) has one of the highest mortality rates despite the advancement of treatment options. Aggressive CRC remains difficult to treat owing to the activation of oncogenic signaling pathways such as the Notch signaling pathway. The role of Notch receptors varies according to the difference in their structures; in particular, aberrant activation of Notch1 has been attributed to the severity of CRC. Notch1 activation in CRC is inhibited by small molecule inhibitors that target γ-secretase, an enzyme responsible for the third and last cleavage step of Notch receptors. γ-Secretase also produces the intracellular domain that finally carries out cellular functions by activating downstream effectors. However, most inhibitors block γ-secretase non-selectively and cause severe toxicity. Plant-source-derived small molecules, monoclonal antibodies, biological molecules (such as SiRNAs), and compounds targeting the Notch1 receptor itself or the downstream molecules such as HES1 are some of the options that are in advanced stages of clinical trials. The Negative Regulatory Region (NRR), which plays a central role in the transduction of Notch1 signaling in the event of ligand-dependent and ligand-independent Notch1 processing is also being targeted specifically by monoclonal antibodies (mAbs) to prevent aberrant Notch1 activation. In this review, we discuss the role of Notch1 in CRC, particularly its metastatic phenotype, and how mutations in Notch1, specifically in its NRR region, contribute to the aberrant activation of Notch1 signaling, which, in turn, contributes to CRC pathogenesis. We also discuss prevailing and emerging therapies that target the Notch1 receptor and the NRR region, and we highlight the potential of these therapies in abrogating Notch signaling and, thus, CRC development and progression. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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51 pages, 1059 KiB  
Review
Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives
by Gillian Moore, Stephanie Annett, Lana McClements and Tracy Robson
Cells 2020, 9(6), 1503; https://doi.org/10.3390/cells9061503 - 20 Jun 2020
Cited by 89 | Viewed by 7536
Abstract
Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and [...] Read more.
Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage. Full article
(This article belongs to the Special Issue The Roles of Notch Signaling in Cancers)
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