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At the Crossroads between Cancer and Cardiovascular Disease: The Notch Pathway

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2019) | Viewed by 24272

Special Issue Editors

Prof. Dr. Paola Rizzo

E-Mail Website
Guest Editor
1. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
2. Laboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, Italy
3. Maria Cecilia Hospital, GVM Care & Research, Cotignola (RA), Italy
Interests: atherosclerosis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Lucio Miele

E-Mail Website
Guest Editor
LSU Health Sciences Center—New Orleans, Louisiana Cancer Research Center, New Orleans, LA, USA
Interests: cancer; precision medicine; breast cancer

Special Issue Information

Dear Colleagues,

Cardiovascular disease and cancer share risk factors affecting the same molecular pathways, including those regulated by Notch receptors. The Notch pathway has been extensively investigated as a novel therapeutic target in oncology, since it regulates cell proliferation, survival, differentiation, stemness, metabolism and angiogenesis, all involved in cancer growth and response to treatment. These same Notch-regulated biological processes are dysregulated in the most common cardiovascular diseases, such as coronary artery disease and heart failure. Compared to the oncology setting, in which several clinical trials are investigating Notch inhibitors as antineoplastic agents, the role of Notch in cardiovascular disease is less characterized and its targeting in this context still at the pre-clinical stage. Based on these shared biological processes, the dissection of the molecular mechanisms regulated by Notch in cancer can be useful for cardiovascular research, and viceversa. This Special Issue is calling for original articles and state-of-the-art reviews that address the major advancements in the field of Notch in cancer and cardiovascular disorders, in order to highlight similarities and differences between the role of Notch in both pathological states, that could speed up the work of basic, translational and clinical researchers in both fields.

Prof. Dr. Paola Rizzo
Prof. Dr. Lucio Miele
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Stemness
  • Metabolism
  • Immunomodulation
  • Metastasis
  • Angiogenesis
  • Apoptosis
  • Authophagy
  • Heart fibrosis
  • Epithelial- and endothelial-mesenchymal transition
  • Endothelial dysfunction
  • Inflammation

Published Papers (4 papers)

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Research

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19 pages, 2511 KiB  
Article
KRIT1 Deficiency Promotes Aortic Endothelial Dysfunction
by Francesco Vieceli Dalla Sega, Raffaella Mastrocola, Giorgio Aquila, Francesca Fortini, Claudia Fornelli, Alessia Zotta, Alessia S. Cento, Andrea Perrelli, Enrica Boda, Antonio Pannuti, Saverio Marchi, Paolo Pinton, Roberto Ferrari, Paola Rizzo and Saverio Francesco Retta
Int. J. Mol. Sci. 2019, 20(19), 4930; https://doi.org/10.3390/ijms20194930 - 05 Oct 2019
Cited by 25 | Viewed by 4531
Abstract
Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence [...] Read more.
Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence demonstrates that KRIT1 is implicated in the modulation of major redox-sensitive signaling pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, suggesting that its loss-of-function mutations may have pathological effects not limited to CCM disease. The aim of this study was to address whether KRIT1 loss-of-function predisposes to the development of pathological conditions associated with enhanced endothelial cell susceptibility to oxidative stress and inflammation, such as arterial endothelial dysfunction (ED) and atherosclerosis. Silencing of KRIT1 in human aortic endothelial cells (HAECs), coronary artery endothelial cells (HCAECs), and umbilical vein endothelial cells (HUVECs) resulted in increased expression of endothelial proinflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and in enhanced susceptibility to tumor necrosis factor alpha (TNF-α)-induced apoptosis. These effects were associated with a downregulation of Notch1 activation that could be rescued by antioxidant treatment, suggesting that they are consequent to altered intracellular redox homeostasis induced by KRIT1 loss-of-function. Furthermore, analysis of the aorta of heterozygous KRIT1+/− mice fed a high-fructose diet to induce systemic oxidative stress and inflammation demonstrated a 1.6-fold increased expression of VCAM-1 and an approximately 2-fold enhanced fat accumulation (7.5% vs 3.6%) in atherosclerosis-prone regions, including the aortic arch and aortic root, as compared to corresponding wild-type littermates. In conclusion, we found that KRIT1 deficiency promotes ED, suggesting that, besides CCM, KRIT1 may be implicated in genetic susceptibility to the development of atherosclerotic lesions. Full article
(This article belongs to the Special Issue At the Crossroads between Cancer and Cardiovascular Disease: The Notch Pathway)
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10 pages, 1311 KiB  
Article
Negative Regulatory Loop between Microphthalmia-Associated Transcription Factor (MITF) and Notch Signaling
by Tamar Golan and Carmit Levy
Int. J. Mol. Sci. 2019, 20(3), 576; https://doi.org/10.3390/ijms20030576 - 29 Jan 2019
Cited by 6 | Viewed by 6016
Abstract
Melanoma, a melanocyte-origin neoplasm, is a highly metastatic and treatment-resistance cancer. While it is well established that notch signaling activation promotes melanoma progression, little is known about the reciprocal interactions between Notch signaling and melanoma-specific pathways. Here we reveal a negative regulatory loop [...] Read more.
Melanoma, a melanocyte-origin neoplasm, is a highly metastatic and treatment-resistance cancer. While it is well established that notch signaling activation promotes melanoma progression, little is known about the reciprocal interactions between Notch signaling and melanoma-specific pathways. Here we reveal a negative regulatory loop between Notch signaling and microphthalmia-associated transcription factor (MITF), the central regulator of melanoma progression and the driver of melanoma plasticity. We further demonstrate that Notch signaling activation, in addition to the known competition-based repression mechanism of MITF transcriptional activity, inhibits the transcription of MITF, leading to a decrease in MITF expression. We also found that MITF binds to the promoter of the gene encoding the master regulator of Notch signaling, recombination signal binding protein J kappa (RBPJK), leading to its upregulation. Our findings suggest that, once activated, Notch signaling represses MITF signaling to maintain the melanoma invasiveness and metastatic phenotype. Full article
(This article belongs to the Special Issue At the Crossroads between Cancer and Cardiovascular Disease: The Notch Pathway)
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Review

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14 pages, 6565 KiB  
Review
Notch Signaling Affects Oral Neoplasm Cell Differentiation and Acquisition of Tumor-Specific Characteristics
by Keisuke Nakano, Kiyofumi Takabatake, Hotaka Kawai, Saori Yoshida, Hatsuhiko Maeda, Toshiyuki Kawakami and Hitoshi Nagatsuka
Int. J. Mol. Sci. 2019, 20(8), 1973; https://doi.org/10.3390/ijms20081973 - 23 Apr 2019
Cited by 7 | Viewed by 5954
Abstract
Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation [...] Read more.
Histopathological findings of oral neoplasm cell differentiation and metaplasia suggest that tumor cells induce their own dedifferentiation and re-differentiation and may lead to the formation of tumor-specific histological features. Notch signaling is involved in the maintenance of tissue stem cell nature and regulation of differentiation and is responsible for the cytological regulation of cell fate, morphogenesis, and/or development. In our previous study, immunohistochemistry was used to examine Notch expression using cases of odontogenic tumors and pleomorphic adenoma as oral neoplasms. According to our results, Notch signaling was specifically associated with tumor cell differentiation and metaplastic cells of developmental tissues. Notch signaling was involved in the differentiation of the ductal epithelial cells of salivary gland tumors and ameloblast-like cells of odontogenic tumors. However, Notch signaling was also involved in squamous metaplasia, irrespective of the type of developmental tissue. In odontogenic tumors, Notch signaling was involved in epithelial–mesenchymal interactions and may be related to tumor development and tumorigenesis. This signaling may also be associated with the malignant transformation of ameloblastomas. Overall, Notch signaling appears to play a major role in the formation of the characteristic cellular composition and histological features of oral neoplasms, and this involvement has been reviewed here. Full article
(This article belongs to the Special Issue At the Crossroads between Cancer and Cardiovascular Disease: The Notch Pathway)
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25 pages, 3888 KiB  
Review
Multifactorial Contribution of Notch Signaling in Head and Neck Squamous Cell Carcinoma
by Cristina Porcheri, Christian Thomas Meisel and Thimios Mitsiadis
Int. J. Mol. Sci. 2019, 20(6), 1520; https://doi.org/10.3390/ijms20061520 - 26 Mar 2019
Cited by 46 | Viewed by 7334
Abstract
Head and neck squamous cell carcinoma (HNSCC) defines a group of solid tumors originating from the mucosa of the upper aerodigestive tract, pharynx, larynx, mouth, and nasal cavity. It has a metastatic evolution and poor prognosis and is the sixth most common cancer [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) defines a group of solid tumors originating from the mucosa of the upper aerodigestive tract, pharynx, larynx, mouth, and nasal cavity. It has a metastatic evolution and poor prognosis and is the sixth most common cancer in the world, with 600,000 new cases reported every year. HNSCC heterogeneity and complexity is reflected in a multistep progression, involving crosstalk between several molecular pathways. The Notch pathway is associated with major events supporting cancerogenic evolution: cell proliferation, self-renewal, angiogenesis, and preservation of a pro-oncogenic microenvironment. Additionally, Notch is pivotal in tumor development and plays a dual role acting as both oncogene and tumor suppressor. In this review, we summarize the role of the Notch pathway in HNSCC, with a special focus on its compelling role in major events of tumor initiation and growth. Full article
(This article belongs to the Special Issue At the Crossroads between Cancer and Cardiovascular Disease: The Notch Pathway)
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