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Special Issue "Activations of Cadherin Signaling in Cancer"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2021).

Special Issue Editor

Dr. Antonella Tomassetti
E-Mail Website
Guest Editor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Unit of Molecular Therapies, Milan, Italy
Interests: signal transduction; cell adhesion; molecular markers; 3D tissue culture; epithelial ovarian cancer
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

The members of the cadherin superfamily are cell–cell adhesion molecules, which are an important determinant of cellular interactions and tissue morphogenesis during development and are essential for the maintenance of adult tissue architecture.

In various types of cancer, cadherins and cadherin-associated or -related proteins are now thought to contribute at different levels to suppression, or initiation, or progression. Indeed, cadherins might act as signaling scaffolds for growth factor signalings, membrane trafficking networks, cytoskeletal remodeling, cell shape and polarity, and gene expression programs, thus positively or negatively contributing to proliferation and cell motility. For metastatic dissemination, the current model involves the process of the epithelial‐to‐mesenchymal transition (EMT), in which cancer cells undergo to the so-called ‘cadherin switch’, partially or completely losing their epithelial properties, detach and move as single cells, and form clonal metastases. Following novel and intriguing investigations, another theory is emerging of collective ‘epithelial metastases’, whereby groups of cancer cells invade and disseminate collectively to establish multiclonal metastases. Other regulatory mechanisms govern cadherin gene expression, trafficking, and processing, and these events integrate with other cellular signaling pathways to drive cancer cell behavior.

This Special Issue calls for original research, full reviews, and perspectives that address, in cancer cells, the current knowledge and the progress in understanding signaling involving cadherins, as well as efforts to develop inhibitors of pro-tumorigenic interactions. Contributions are not limited to the fields mentioned in the keywords.

Dr. Antonella Tomassetti
Guest Editor

Manuscript Submission Information

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Keywords

  • Cadherin
  • Catenin, actin cytoskeleton
  • EMT
  • Proliferation
  • Migration
  • Invasion
  • Metastasis
  • Gene expression
  • Protein degradation

Published Papers (8 papers)

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Research

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Article
Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins
Int. J. Mol. Sci. 2019, 20(23), 5958; https://doi.org/10.3390/ijms20235958 - 27 Nov 2019
Cited by 3 | Viewed by 1060
Abstract
Cadherins are a major family of cell–cell adhesive receptors, which are implicated in development, tissue homeostasis, and cancer. Here, we show a novel mechanism of post-translational regulation of E-cadherin in cancer cells by an intramembrane protease of the Rhomboid family, RHBDL2, which leads [...] Read more.
Cadherins are a major family of cell–cell adhesive receptors, which are implicated in development, tissue homeostasis, and cancer. Here, we show a novel mechanism of post-translational regulation of E-cadherin in cancer cells by an intramembrane protease of the Rhomboid family, RHBDL2, which leads to the shedding of E-cadherin extracellular domain. In addition, our data indicate that RHBDL2 mediates a similar activity on VE-cadherin, which is selectively expressed by endothelial cells. We show that RHBDL2 promotes cell migration, which is consistent with its ability to interfere with the functional role of cadherins as negative regulators of motility; moreover, the two players appear to lie in the same functional pathway. Importantly, we show that RHBDL2 expression is induced by the inflammatory chemokine TNFα. The E-cadherin extracellular domain is known to be released by metalloproteases (MMPs); however, here, we provide evidence of a novel MMP-independent, TNFα inducible, E-cadherin processing mechanism that is mediated by RHBDL2. Thus, the intramembrane protease RHBDL2 is a novel regulator of cadherins promoting cell motility. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Article
E-cadherin Downregulation and microRNAs in Sporadic Intestinal-Type Gastric Cancer
Int. J. Mol. Sci. 2019, 20(18), 4452; https://doi.org/10.3390/ijms20184452 - 10 Sep 2019
Cited by 9 | Viewed by 1405
Abstract
CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) [...] Read more.
CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated CDH1 expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (p-value = 0.025). Moreover, 14 miRs, predicted to be involved in CDH1 regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (p-value < 0.001). Finally, we evaluated EZH2 expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (p-value = 0.005). A significant inverse correlation was observed between EZH2 overexpression and CDH1, miR-101, and miR-26b levels (p-value < 0.001). Our results reinforce the link between CDH1 and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Article
Cdh4 Down-Regulation Impairs in Vivo Infiltration and Malignancy in Patients Derived Glioblastoma Cells
Int. J. Mol. Sci. 2019, 20(16), 4028; https://doi.org/10.3390/ijms20164028 - 18 Aug 2019
Cited by 9 | Viewed by 1266
Abstract
The high invasive phenotype of glioblastoma is one of the main causes of therapy inefficacy and tumor relapse. Cell adhesion molecules of the cadherin family are involved in cell migration and are known as master regulators of epithelial tumor invasiveness, but their role [...] Read more.
The high invasive phenotype of glioblastoma is one of the main causes of therapy inefficacy and tumor relapse. Cell adhesion molecules of the cadherin family are involved in cell migration and are known as master regulators of epithelial tumor invasiveness, but their role in glioblastoma is less understood. In particular, we recently demonstrated, in the syngeneic murine model, the occurrence of a previously undescribed cadherin switch between Cdh2 and Cdh4 during gliomagenesis, which is necessary for the acquisition of the highly infiltrative and tumorigenic phenotype of these cells. In the present study, we tested the role of Cdh4 in human gliomas. Our results on patient-derived glioma cells demonstrate a positive correlation between Cdh4 expression levels and the loss of cell–cell contact inhibition of proliferation controls that allows cells to proliferate over confluence. Moreover, the silencing of Cdh4 by artificial microRNAs induced a decrease in the infiltrative ability of human glioma cells both in vitro and in vivo. More strikingly, Cdh4 silencing induced an impairment of the tumorigenic potential of these cells after orthotopic transplantation in immunodeficient mice. Overall, we conclude that in human glioblastoma, Cdh4 can also actively contribute in regulating cell invasiveness and malignancy. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Article
Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion
Int. J. Mol. Sci. 2019, 20(14), 3404; https://doi.org/10.3390/ijms20143404 - 11 Jul 2019
Cited by 10 | Viewed by 2160
Abstract
Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A [...] Read more.
Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell–cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell–cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell–cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Review

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Review
Role of Cadherins in Cancer—A Review
Int. J. Mol. Sci. 2020, 21(20), 7624; https://doi.org/10.3390/ijms21207624 - 15 Oct 2020
Cited by 18 | Viewed by 1699
Abstract
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin [...] Read more.
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Review
Tumor-Derived Exosomes Mediate the Instability of Cadherins and Promote Tumor Progression
Int. J. Mol. Sci. 2019, 20(15), 3652; https://doi.org/10.3390/ijms20153652 - 26 Jul 2019
Cited by 17 | Viewed by 1787
Abstract
Cadherins, including E-cadherin, N-cadherin, VE-cadherin, etc., are important adhesion molecules mediating intercellular junctions. The abnormal expression of cadherins is often associated with tumor development and progression. Epithelial–mesenchymal transition (EMT) is the most important step in the metastasis cascade and is accompanied by altered [...] Read more.
Cadherins, including E-cadherin, N-cadherin, VE-cadherin, etc., are important adhesion molecules mediating intercellular junctions. The abnormal expression of cadherins is often associated with tumor development and progression. Epithelial–mesenchymal transition (EMT) is the most important step in the metastasis cascade and is accompanied by altered expression of cadherins. Recent studies reveal that as a cargo for intercellular communication, exosomes—one type of extracellular vesicles that can be secreted by tumor cells—are involved in a variety of physiological and pathological processes, especially in tumor metastasis. Tumor-derived exosomes play a crucial role in mediating the cadherin instability in recipient cells by transferring bioactive molecules (oncogenic microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), EMT-related proteins, and others), modulating their local and distant microenvironment, and facilitating cancer metastasis. In turn, aberrant expression of cadherins in carcinoma cells can also affect the biogenesis and release of exosomes. Therefore, we summarize the current research on the crosstalk between tumor-derived exosomes and aberrant cadherin signals to reveal the unique role of exosomes in cancer progression. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Review
Beyond N-Cadherin, Relevance of Cadherins 5, 6 and 17 in Cancer Progression and Metastasis
Int. J. Mol. Sci. 2019, 20(13), 3373; https://doi.org/10.3390/ijms20133373 - 09 Jul 2019
Cited by 14 | Viewed by 2801
Abstract
Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work [...] Read more.
Cell-cell adhesion molecules (cadherins) and cell-extracellular matrix adhesion proteins (integrins) play a critical role in the regulation of cancer invasion and metastasis. Although significant progress has been made in the characterization of multiple members of the cadherin superfamily, most of the published work continues to focus in the switch E-/N-cadherin and its role in the epithelial–mesenchymal transition. Here, we will discuss the structural and functional properties of a subset of cadherins (cadherin 17, cadherin 5 and cadherin 6) that have an RGD motif in the extracellular domains. This RGD motif is critical for the interaction with α2β1 integrin and posterior integrin pathway activation in cancer metastatic cells. However, other signaling pathways seem to be affected by RGD cadherin interactions, as will be discussed. The range of solid tumors with overexpression or “de novo” expression of one or more of these three cadherins is very wide (gastrointestinal, gynaecological and melanoma, among others), underscoring the relevance of these cadherins in cancer metastasis. Finally, we will discuss different evidences that support the therapeutic use of these cadherins by blocking their capacity to work as integrin ligands in order to develop new cures for metastatic patients. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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Review
E-cadherin Beyond Structure: A Signaling Hub in Colon Homeostasis and Disease
Int. J. Mol. Sci. 2019, 20(11), 2756; https://doi.org/10.3390/ijms20112756 - 05 Jun 2019
Cited by 22 | Viewed by 2765
Abstract
E-cadherin is the core component of epithelial adherens junctions, essential for tissue development, differentiation, and maintenance. It is also fundamental for tissue barrier formation, a critical function of epithelial tissues. The colon or large intestine is lined by an epithelial monolayer that encompasses [...] Read more.
E-cadherin is the core component of epithelial adherens junctions, essential for tissue development, differentiation, and maintenance. It is also fundamental for tissue barrier formation, a critical function of epithelial tissues. The colon or large intestine is lined by an epithelial monolayer that encompasses an E-cadherin-dependent barrier, critical for the homeostasis of the organ. Compromised barriers of the colonic epithelium lead to inflammation, fibrosis, and are commonly observed in colorectal cancer. In addition to its architectural role, E-cadherin is also considered a tumor suppressor in the colon, primarily a result of its opposing function to Wnt signaling, the predominant driver of colon tumorigenesis. Beyond these well-established traditional roles, several studies have portrayed an evolving role of E-cadherin as a signaling epicenter that regulates cell behavior in response to intra- and extra-cellular cues. Intriguingly, these recent findings also reveal tumor-promoting functions of E-cadherin in colon tumorigenesis and new interacting partners, opening future avenues of investigation. In this Review, we focus on these emerging aspects of E-cadherin signaling, and we discuss their implications in colon biology and disease. Full article
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)
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