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Cadherin Signaling in Cancer: Its Functions and Role as a Therapeutic Target

Weina Yu, Li Yang, Ting Li and 1 more

Frontiers in Oncology · 2019 · Review · CC BY

doi:10.3389/fonc.2019.00989

Abstract

Cadherin family includes lists of transmembrane glycoproteins which mediate calcium-dependent cell-cell adhesion. Cadherin-mediated adhesion regulates cell growth and differentiation throughout life. Through the establishment of the cadherin-catenin complex, cadherins provide normal cell-cell adhesion and maintain homeostatic tissue architecture. In the process of cell recognition and adhesion, cadherins act as vital participators. As results, the disruption of cadherin signaling has significant implications on tumor formation and progression. Altered cadherin expression plays a vital role in tumorigenesis, tumor progression, angiogenesis, and tumor immune response. Based on ongoing research into the role of cadherin signaling in malignant tumors, cadherins are now being considered as potential targets for cancer therapies. This review will demonstrate the mechanisms of cadherin involvement in tumor progression, and consider the clinical significance of cadherins as therapeutic targets.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Cadherin was first described by Hyafil and Peyrieras in the 1980s as “Uvomorulin” in mouse and L-CAM in chicken and the mouse gene was later cloned. Subsequently, several other cadherins were found and analyzed, including N-cadherin (CDH1), which is mainly expressed in neural tissue, and P-cadherin (CDH3), which was first characterized from placental tissue. Many subtypes have since been identified in other species and there are now more than 100 known members in this superfamily.

Functionally, cadherins act as modulators during organism growth. First, tissue cohesion in organisms depends largely on cadherins. Radice et al. found that mice lacking N-cadherin (CDH2) developed heart defects and died in utero. Moreover, cadherins affect cell polarization, by differentiating between cell populations during development; this function might has a relationship with intrinsic characteristics of the ectodomains of cadherins.

The research to date has focused on the relationship between cadherins and malignant tumors, and drugs targeting cadherins have been developed and tested in clinical trials. In this review, we intend to summarize the mechanisms whereby cadherins mediate tumor formation and progression, and to discuss their potential use in clinical treatment of cancer patients.

Types of Cadherin

Cadherins can be classified into several subtypes: type I classical cadherins such as E-cadherin, N-cadherin, and P-cadherin; type II classical cadherins such as VE-cadherin (CDH5) and OB-cadherin (CDH11); the desmosomal cadherins; the seven-pass transmembrane cadherins; FAT and dachsous (DCHS) group cadherins; and protocadherins (PCDHs) (Table 1). Nearly all cadherins are transmembrane proteins with three components: (1) an extracellular cadherin domain (EC) responsible for homotypic cadherin-cadherin interaction; (2) a single-pass transmembrane domain (absent in seven-pass transmembrane cadherins); and (3) a cytoplasmic domain acts as a connector between cell surface and cytokeleton (Figure 1).

Classical cadherins like E-cadherin, P-cadherin and N-cadherin, which translate the intercellular contact signals involved in cellular organization, are mediated mainly by the catenins, namely α-catenin, β-catenin, and γ-catenin, which are membrane undercoat proteins that link the tail of cadherins in the cytoplasm (Figure 1). VE-cadherin binds to other proteins such as plakoglobin, which binds and recruits a desmosomal plaque protein named desmoplakin to the cell surface; vinculin also participates in this process. In tissues that undergo greater mechanical strain, such as the epidermis and myocardium, desmosomal cadherins function through plakoglobin, desmoplakin, and the armadillo family member plakophilins, to mediate the linkage between the cytoskeleton and these proteins. Protocadherin can be divided into two subfamilies—clustered and non-clustered protocadherins (Table 1). Clustered protocadherins have a unique binding site for non-receptor tyrosine kinase Fyn, one of the Src kinases families in the cytoplasm. Non-clustered protocadherins include three types: δ1 (e.g., PCDH7), δ2 (e.g., PCDH8), and ε (e.g., PCDH15). PCDH7 has three motifs, all of which can interact with the histone-regulating protein template-activating factor 1 and protein phosphatase-1α, and is inactivated when it binds to the CM3 motif. PCDH8 can interact with thousand and one amino acid protein kinase 2β through its intracellular domain, thereby activating the p38 MAPK pathway, which may enhance endocytosis of N-cadherin (Figure 1). The flamingo cadherin differs from the other cadherins—it has a transmembrane domain that spans the plasma membrane seven times, somewhat like that of G proteins, and participates in many cellular signaling pathways (Figure 1). Fat and dachsous cadherins are very large cell-adhesion molecules (Table 1); a recent study showed the involvement of Fat cadherin in the Wnt-signaling pathway with the help of β-catenin (Figure 1).

Cadherins and Tumorigenesis

In the developmental process of multicellular organisms, the maintaining of cellular and tissue morphogenesis mainly depends on cell-cell adhesion, which initiated and maintained by adheren junction. The signaling mediated by adhesion between cell-cell and cell-extracellular matrix is associated with gene regulation in normal tissue homeostasis. Disturbance of cell-cell and cell-extracellular matrix adhesion and the subsequent changes in adhesion-mediated signaling pathways would induce malignant phenotypes in normal cells.

As a major contributor to cell–cell adhesion in epithelial tissues, abnormal expression of cadherins is closely related to tumorigenesis. β- and γ-catenin are bridges that mediate linkage of classical cadherins to the actin cytoskeleton through their cytoplasmic domains. It has been shown that cell–cell adhesion is markedly reduced when a well-differentiated benign adenoma with apico-basal polarization, a feature of normal epithelial cells, becomes an invasive carcinoma by losing its normal membrane polarization. Many signaling pathways are involved in this process. Epithelial–mesenchymal transition (EMT), a phenotype transition, is a driving force in tumorigenesis.

E-cadherin and N-cadherin are founding members of the cadherin superfamily and act as crucial regulators in the process of tumor development. E-cadherin is essential in maintaining epithelial tissue integrity and providing strength to maintain polarization of the epithelial cell layers. N-cadherin is highly expressed in mesenchymal cells and neural tissue. N-cadherin promotes increased cell motility and migration, by interacting with epidermal growth factor receptor (EGFR) 1 via the 88-amino acid region of the EC4 domain. During malignancy, cell–cell adhesion mediated by E-cadherin is lost, and this process can be reversed when E-cadherin is re-established. These studies propose the novel view that EMT can participate in the development of malignant tumors.

Many factors can lead to E-cadherin loss. Some of cancer associated germline mutations had been reported to interfere the expression and function of cadherin. Additionally, in many epithelial malignancies like esophagus, melanoma, and hepatocellular carcinoma, the expression of E-cadherin is decreased by the hypermethylation of promoter. Besides, the frequent loss of p120 expression would cause the degradation of E-cadherin in lung cancer. As a result, the expression of β-catenin would upregulate along with the reduction of E-cadherin and downstream signaling pathways associated with tumorigenesis in nuclear would be activated by the elevated β-catenin. However, E-cadherin loss by itself is insufficient to stimulate the following signaling pathway due to the decrease mechanism of β-catenin which mediated by Wnt signaling pathway (Figure 2A). In this degradation process, glycogen synthase kinase (GSK) phosphorylates β-catenin and induces its ubiquitination and degradation in the 26 S proteasome to keep the low level of β-catenin in cytoplasm, as well as cell nucleus. After Wnt proteins bind to Frizzled, the signaling pathway is activated (Figure 2A). The disheveled protein then binds, resulting in failure of degradation of the complex and block the degradation effects casein kinase 1 α and GSK3 on β-catenin. Thus, β-catenin accumulates in the cytoplasm and is translocated to the nucleus, where it competitively inhibits a suppresser of T-cell factor/lymphoid enhancer factor (TCF/LEF) and could active Wnt-responsive genes. Additionally, some co-activators in transcription, such as p300, CREB-binding protein and B-cell lymphoma 9, could be stimulated at the same time. N-cadherin has a physical association with and could stimulate the MAPK/ERK signaling pathway, which participates in tumorigenesis (Figure 2A).

One possible explanation for the role of EMT in this transition is that ectopically expressed N-cadherin may promote the migration of epithelial cells with a similar cadherin expression profile, and thereafter act in an entirely different way. On the other hand, altered cadherin expression may affect intracellular signaling, causing depolarization of cells and enhanced migratory properties. Many factors participate in this process. For example, The E-cadherin/β-catenin complex functions as an intercellular junction and is regulated by phosphorylation. Phosphorylation by Src or epithelial growth factor receptor destroys the binding between β-catenin and cadherin, and subsequently enhances the expression of cytoplasmic β-catenin, which activates Wnt/β-catenin signaling. It has been reported that abnormal activation of this pathway may induce tumor formation, by binding with TCF/LEF-type transcription factors and stimulating cancer-related genes such as c-MYC and CCND1, which may affect the cell cycle and promote tumorigenesis (Figure 2). N-cadherin has also been reported to be physically associated with various members of the fibroblast growth factor receptor (FGFR) family, and to participate in increasing the cell-surface receptor level and sustaining MAPK/ERK signaling, thus increasing cellular motility and invasion.

Other types of cadherins have similar effects in malignant tumor formation. For example, the role of P-cadherin in human cancer has been debated for years. Moreover, loss of P-cadherin has a significant correlation with histological tumor staging. In a P-cadherin-null mouse model, mammary glands developed hyperplasia, dysplasia, and abnormal lymphoid infiltration, demonstrating that P-cadherin expression is important in maintaining normal tissue. Similarly, Hardy et al. found that in colonic lesions, regulation of P-cadherin differs from that of E-cadherin during colonocyte transformation; P-cadherin was expressed in low-malignancy potential lesions, indicating that P-cadherin is unlikely to participate directly in tumorigenesis. Similarly, H-cadherin participate in the carcinogenesis of colorectal cancer.

Therefore, cadherins function not only as the molecules of cell-cell adhesion but also as factors which induce tumorigenesis predominantly through Wnt/β-catenin or other signaling pathways.

Cadherins and Tumor Progression

Once cell-cell adhesion was disrupted, adhesion-mediated signaling pathways would be changed subsequently. Some characteristics in invasive metastatic cancer, such as cell mobility, would be affected as well. Cadherins have been implicated in tumorigenesis, and research into their roles in tumor progression should not be neglected. It is widely accepted that EMT of epithelial cells results in the feature of strong cell-cell adhesion and more motile and invasive characteristics. A feature of EMT is the downregulation of E-cadherin and parallel upregulation of other cadherins, like N-cadherin, which plays a key role during early invasion and metastasis.

E-cadherin and Tumor Progression

Many researches have proved that E-cadherin expression is often lost in advanced tumors; this may be associated, at least in some instances, with increased metastasis and recurrence. It had been demonstrated in vitro that downregulation of E-cadherin is related to the loss of epithelial phenotype and the acquisition of the mesenchymal phenotype, which is associated with invasive behavior; this has been validated using 3D gels and heart explants. Further, partial or complete reversal of this process occurs when E-cadherin is constitutively produced.

The E-cadherin–catenin complex was the first signaling pathway to be studied. Many factors affecting this complex participate in reduced cell adhesion, which is of great importance during tumor metastasis; these factors include reduction, loss, or redistribution of E-cadherin, and mutation or reduced transcription of the related genes. Similarly, many factors lead to downregulation of E-cadherin-mediated cell adhesion; these include hepatocyte growth factor, epithelial growth factor, and TGF-β, which are thought to initiate EMT and upregulate EMT-related transcriptional factors such as Snail, Slug, and T-wist (Figure 2). This downregulation reduces cell–cell adhesion, and an oncogenic stimulus via β-catenin, further stimulating the canonical Wnt signaling pathway, and finally stimulating TCF-regulated genes. TCF-regulated genes, which are key factors in cell proliferation and invasion, including CCND1, MMP-7, MMP14, FN1, c-MYC, LGR5, PLAUR etc.. The non-canonical Wnt pathway may also influence cancer metastasis, and overexpression of Wnt5a is responsible for enhanced cell migration and resistance to treatment (Figure 2). Further, crosstalk involved in cell–cell communication and cell-matrix adhesion can be regulated by several signaling pathways that affect the migratory and invasive ability of cells by disrupting adherens junctions when integrins are activated. For example, a downstream factor of integrin focal adhesion kinase–Src regulates TGF-β-induced EMT, and is involved in coupling integrin activation with TGF-β-induced EMT. E-cadherin also plays a role in cancer progression itself, partially through the PI3K-AKT and MEK-ERK pathways. Integrin functions as a cell–cell adhesion molecular and its interaction with P-cadherin increases migration (Figure 2B).

However, Kowalski et al. hold the view that abnormal E-cadherin expression is more common in invasive ductal carcinomas with the potential to develop distant metastases. E-cadherin expression in more consistent and often more frequent in distant metastases than in the primary cancer. Therefore, it is possible that E-cadherin protein is re-expressed once cancer cells reach distant sites. In the study from Bukholm et al., 95% metastatic lymph nodes were highly expressed E-cadherin. The expression or re-expression of E-cadherin in distant metastases of invasive cancer suggests that it may contribute to the establishment of metastatic foci.

N-cadherin and Tumor Progression

The other key factor involved in EMT is N-cadherin. A major consequence of EMT is the loss of stable adhesive junctions of epithelial cells, the reversion of normal polarity among cells, and the destruction of epithelial tissue structure, therefore accelerating the migration of malignant tumor cells toward adjacent tissues. Unlike E-cadherin, N-cadherin upregulation enhances the migratory and invasive capacities of tumor cells. N-cadherin is as important as E-cadherin in development and adulthood. Besides, during tumor progression, N-cadherin can affect cell survival, facilitate the process of EMT and migration/invasion by recruiting signaling molecules. Crosstalk of N-cadherin with other membrane protein such as fibroblast growth factor receptor (FGFR) also activates signaling cascades that affect cell proliferation, invasion, and cell–cell adhesion (Figure 2B). In normal epithelial cells, N-cadherin is absent or expressed at low levels, and aberrant expression is associated with malignancies and tumor progression. Using an orthotopic mouse model, Shintani et al. showed that, compared to N-cadherin cancer cell lines, N-cadherin-knockdown cancer cells formed significantly smaller primary tumors and micrometastases in lungs. A similar result was found by Bouvet et al.. In E-cadherin–positive cancer cell lines, overexpression of N-cadherin made cells more invasive both in vitro and in vivo, but did not cause parallel downregulation of E-cadherin. These results suggest that N-cadherin may promote cancer metastasis even without the presence of E-cadherin.

Many signaling pathways participate in the process of malignancy. Hulit et al. found that mammary epithelium tumors had greater metastatic potential in PyVmT transgenic mice with N-cadherin expression than in those without it. Further, PyVmT transgenic mice with N-cadherin expression showed greater ERK activation, and migration and invasion, and increased matrix metalloprotein-9 expression, than those without N-cadherin expression. Further, when FGFR was blocked in the PyVmT transgenic mice with N-cadherin expression, motility and invasion were reduced, as was ERK phosphorylation. Similar results have been found in several other cell lines that co-express N-cadherin and FGFR-1, suggesting that the FGFR-N-cadherin signaling pathways might be general routes involved in metastasis. These results reveal a signaling cascade, N-cadherin/FGFR/MAPK/ERK/ matrix metalloprotein-9, in which N-cadherin mediates metastasis.

Other Cadherins and Tumor Progression

Aside from the two classical cadherins, other types of cadherins can also participate in metastasis. Despite its role in the maintenance of tissue architecture, studies are increasingly revealing that P-cadherin dysfunction is strongly associated with tumorigenesis and confers the malignant phenotype in cancer cells. Mandeville et al. revealed that P-cadherin can modulate the migratory ability of bladder carcinoma cells in vitro. Similarly, Taniuchi et al. demonstrated that, in the vast majority of pancreatic ductal adenocarcinoma cells examined, overexpression of P-cadherin altered the subcellular localization of the p120 catenin, and increased the steady-state activity of Rho GTPases. Those changes were associated with increased motility of pancreatic ductal adenocarcinoma cells. In the liver metastatic site of colon cancer, P-cadherin expression was much higher compared to primary site; P-cadherin knockdown affected wound healing, proliferation, and colony formation, and inhibited liver metastatic foci formation in vivo.

OB-cadherin belongs to the type II cadherin subfamily, and is related to a poor prognosis. OB-cadherin interacts with α- and β-catenin in vivo and may play a role in connecting to the cell-matrix, especially in promoting cell extension. Therefore, OB-cadherin may participate in promoting invasion and metastasis of malignant tumor via the interaction with fibroblasts or osteoblasts in the stroma and bone.

Bartolomé et al. pointed out that the Arg-Gly-Asp motifs of VE-cadherin activate the α2β1 integrin, and then promote cell adhesion, cancer invasion, proliferation, and lung metastasis. It has been revealed that higher expression of VE-cadherin leads to poor prognosis in breast cancer and melanoma patients. These results suggest the novel concept that therapies that target cadherin-specific Arg-Gly-Asp motifs may control distant metastasis in multiple cancers.

The role of PCDHs in cancer progression is complicated. Several studies have mentioned that PCDHs could induce apoptosis of tumor cells and prevent malignant tumor from proliferating and metastasis. This point of view has been approved in colon cancer. Similarly, based on in vitro testing, restoration of PCDH9 expression has effects on cell cycle and could strength apoptosis. So do PCDH20 and PCDH17. When PCDHs are lost, tumor cells gain a more aggressive phenotype. For example, loss of PCDH10 significantly enhances the proliferation of myeloma cells and may act as a prognostic marker for the reduced survival of colorectal cancer patients. More specifically, when PCDH17 was lost, it could stimulate EGFR/MEK/ERK signaling pathway and accelerate the progression of liver cancer. Recent research has elucidated the oncogenic activity of PCDHs. It has been reported that PCDH7 is significantly increased in breast cancer and has a positive correlation with brain metastases. Further, Chen et al. and Terry et al. found PCDH-PC, a cytoplasmically retained variant of PCDH11Y, was upregulated in advanced prostate cancer and metastasis. The specific mechanisms whereby PCDHa affect cancer remain to be studied.

In brief, cadherins, especially E-cadherin and N-cadherin, participate in EMT and thus regulate tumor invasion and metastasis.

Cadherins and Angiogenesis

Malignant tumors consume much more energy and oxygen than normal tissues and need fast-growing vascular networks to support the proliferation of tumor. In this process, various types of pro-angiogenic factors are secreted by tumor cells and stromal cells and help building abnormal vascular networks which are disorganized, immature and permeable, leading to inadequately perfused malignant tumors. In the development of malignant tumor, cadherins do more than just providing adhesion. They interact with many cytoskeletal and signaling molecules by transferring signals into cells. Endothelial cells present different cadherins which may transfer specific signals and have distinct functional roles.

VE-cadherin, originally called cadherin-5, is mainly located in vascular endothelial cells and is indispensable for vascular building during embryonic development. In addition to being a transmembrane component of the endothelial cadheren junction, it maintains the integrity and permeability of the endothelium and vascular system. Thus, a burst of VE-cadherin expression may be required in promoting and sustaining vascular growth.

VE-cadherin promotes tumor progression mainly by facilitating tumor angiogenesis. VE-cadherin could interact with vascular endothelial growth factor receptor (VEGFR)-2 (Figure 2C) and stimulate TGF-β signaling pathway to enhance cell proliferation. Many growth factors such as VEGF could induce the tyrosine phosphorylation of VE-cadherin, β-catenin and p120, which would increase vascular permeability in vitro system. VE-cadherin phosphorylation through the VEGF/VEGF R2 pathway needs Src activity (Figure 2C). In angiogenic tissues, VE-cadherin-associated Src phosphorylation is increased and inhibition of Src inhibits VEGF-stimulated vascular permeability. With the help of other phosphatases, VEGF 2R and Src lead to the phosphorylation of VE-cadherin on tyrosines and this association would induce endothelial cell survival through PI3K/AKT pathway (Figure 2C). However, in the absence of protein tyrosine phosphatase activity, ERK/MAPK pathway is activated to stimulate cell proliferation (Figure 2C). Similarly, VE-cadherin can interact with the TGF-receptor complex, platelet-derived growth factor β-receptor, or FGFR1, among others, and may affect the proliferation of endothelial cells and stability of vascular structures.

N-cadherin functions mainly as a promoter of malignant tumors. However, the role it plays in tumor angiogenesis should not be underestimated. N-cadherin affects vascular tissue mainly by interacting with pericytes and vascular smooth muscle cells in the endothelium. Unlike VE-cadherin, which predominates in vascular epithelial cells, N-cadherin predominates in pericytes. In chickens, once N-cadherin is neutralized or lost, defective pericyte adhesion occurs causing aberrant vascular development. The amount of VE-cadherin expressed depends on N-cadherin, and N-cadherin affects vascular morphogenesis by regulating VE-cadherin, suggesting that N-cadherin is a crucial regulator of angiogenesis.

Nalla et al. found that N-cadherin knockdown suppressed the expression of several angiogenic molecules and reduced the angiogenic ability of PC3 cells, which indicates that endothelial cell is not the only target of N-cadherin, angiogenesis could also be promoted by N-cadherin through regulating chemokines and angiogenic molecules. Doherty et al. have found that N-cadherin has an His–Ala–Val (HAV) sequence in the extracellular domain directly linked to the HVA sequence present on FGFR (Figure 2C) and propose that trans-interactions between N-cadherin molecules on cell membranes trigger cis-interactions between N-cadherin complexes and FGFR monomers, subsequently causing FGFR dimerization and activation. Thus, N-cadherin-mediated endothelial cell adhesion may facilitate angiogenesis. Similarly, a soluble 90 kDa fragment of N-cadherin promoted angiogenesis in an FGFR-dependent manner. Proteases cleave the extracellular part of N-cadherin and produce soluble N-cadherin. Soluble N-cadherin can phosphorylate ERK and stimulate angiogenesis (Figure 2C).

In conclusion, cadherins play a vital role in tumor angiogenesis mainly through binding to VEGFR or platelet-derived growth factor receptor in order to affect vascular structures.

Cadherins and Tumor Immune Response

A tumor is not a one step result; the role of host immunity in the formation and progression of maglinant tumor s is complex and should not be negelected. Solid tumors are commonly infiltrated by a large number of immune cells which funtion seems pretty paradoxical. Once the microcolonies of malignant cells were detected by immune system, innate and adaptive immune cells would be able to eradicate them. However, genome plasticity renders some tumor cells the ability to proliferate continuously and thus cause an equilibrium between the generating and eradicating of tumor cells. The continuing proliferation of tumor cells would finally cause a broken equilibrium along with detectable tumor followed by metastasis. Concomitantly, surviving tumor clones control immune responses by specifically suppressing anti-tumor effector mechanisms and accumlating immunosuppressive immune cell subsets, inculding DCs, tumor-associated macrophages and Tregs at the tumor site.

Viollet et al. hold the view that E-cadherin participates in the maintaining of epithelial barrier and prevents potentially harmful agents from inner tissue. This is the immunologic function of E-cadherin. Furthermore, E-cadherin might take part in the regulation of epithelial innate immune function through multiple chemokines and cytokines and modulating transepithelial transfer of immunes cells. Recent studies have shown that cadherins are highly expressed in several leukocytes, such as dendritic cells (DCs), macrophages and Langerhans cells.

DCs are important participators in adaptive immunity. The roles of cadherins in DCs have been investigated. It is widely recognized that E-cadherin is expressed in Langerhans cells, a type of immature DC. As DCs mature, their expression of E-cadherin is reduced to facilitate the migration of DCs to the lymphoid organs. Infiltration of DCs occurs in solid tumors, and E-cadherin expression in DCs may be upregulated by tumor cells; this upregulation is thought to inhibit the function of DCs in presenting tumor antigens. Jiang et al. showed that bone marrow-derived DC (BMDC) express E-cadherin, and BMDC activation would be induced when E-cadherin-depended DC-DC interaction was disrupted. This would upregulate the expression of costimulatory molecules and CCR7, downregulate the macropinocytosis, and lead to the migration of MHC II molecules from lysosomes to cell surface. At the same time, loss of E-cadherin results in the accumulation of cytoplasmic β-catenin and stimulates the following signaling pathways like TCF. Manicassamy et al. showed that β-catenin deletion in DC would accumulates Th1 and Th17 cell infiltation in intestine of mice, and decrease the number of regulatory T cells. This indicates that E-cadherin plays a significant role in DCs and may affect their functions in the tumor microenvironment.

Macrophages are involved in the whole process of life via phagocytic ability and producing immunoregulatory mediators and trophic. They could also recognize, engulf and destruct pathogens to facilitate tissue development and recognition and maintain homeostasis. According to the research of Rehli et al., IL-4 could induce the expression of E-cadherin, which was considered as a marker of M2 macrophages, in mouse bone marrow-derived macrophages (in vitro) and several mice models (in vivo).

In specimens of sarcoidosis and foreign body granulomas from humans, E-cadherin is expressed in skin granuloma macrophages. In an in vitro experiment, IL-4/IL-13 induced macrophages to express E-cadherin. In Th2-driven diseases, IL-4 and IL-3 are crucial for inducing E-cadherin in both mouse and human macrophages. However, in the tumor microenvironment, E-cadherin expression is higher and independent of IL-4/IL-13 in M1-like macrophages, in contrast to the situation in M2-like macrophages. One possible reason is that M2-like macrophages are preindominantly accumulated in the hypoxic areas of tumor tissue, which reported to reduce E-cadherin expression. Further, E-cadherin may contribute to the process of fusion and engulfment in macrophages: β-catenin is barely detectable in naïve macrophages due to the absence of E-cadherin, but is found to be stable in the E-cadherin/β-catenin complex after stimulated with IL-4, which could enhance the fusion and engulfment of pathogens in macrophages in a STAT5-dependent way. Thus, E-cadherin might act as a promoter in helping macrophages to kill tumor cells.

The classical cadherin pathways, including Wnt, PI3K, Rho-family GTPases, and NF-κB, operate in macrophages and DCs. Besides, Wnt/β-catenin has been reported to contribute to the anti-inflammatory phenotype of macrophages and tolerogenic state of DCs. When Wnt binds to Frizzled, the phosphorylation of β-catenin by casein kinase 1 and GSK-3β is inhibited, leading to an upregulation of nuclear β-catenin and activation of TCF/LEF-dependent gene expression, which stimulates anti-inflammatory macrophages and tolerogenic DCs (Figure 2D). And at the same time, other pathways can also influence macrophage and DC functioning. It has been shown that E-cadherin could suppress the activity of macrophages and DCs via PI3K/AKT signaling pathway. In addition, NF-κB, a vital transcription factor, could also be regulated by E-cadherin-catenin in macrophages and DCs, using p120 catenin as a docking site and working as a suppresser (Figure 2D).

On the surface of other immune cells, including CD8+ T, NK, and regulatory T cells, there are various ligands that can bind to the E-cadherin expressed on DCs and macrophages. For example, killer cell lectin-like receptor G1 (KLRG1) binds to the N-terminal homodimeric interface of E-cadherin EC1. KLRG1 is expressed mainly on the surface of mature NK cells, and its activation inhibits NK cytotoxicity. Furthermore, KLRG1 has been found on CD4+ T cells and CD8+ T cells and regulates T cell responses to suboptimal conditions. The integrin αE chain, also known as CD103, is a ligand expressed mainly on intraepithelial αβ and γδ T cells, and mediates the adhesion between E-cadherin+ epithelial cells and T cells in vitro (Figure 2).

In shortly, besides the effect on tumor cells, cadherins also participate in regulating various immune cells in the tumor microenvironment. However, further study is needed to illuminate the role of cadherins in tumor-associated immune cells.

Therapeutic Targets in Cancer

It has been reported that many signaling pathways or proteins are abnormally activated in malignant tumor cells, so molecular-targeted therapy has been developed and achieved pretty good response in cancer patients recent years. Those molecular-targeted drugs are able to kill cancer cell selectively with decreased toxicity on normal cell, which is the significant improvement comparing with traditional anticancer drugs. Targeted drugs inhibit specific signaling pathways that contribute to the malignant phenotype of cancer cells and limit the progression of malignant tumors. Cadherins, vital molecules in tumorigenesis and cancer progression, could be also worked as therapeutic targets in cancer treatment.

Inhibition of Angiogenesis

Generation of new vascular network tissue is of great importance for tumors because of their high proliferative rate. As a result, targeting tumor blood vessels is a feasible strategy in cancer therapy. Specific antibodies of VE-cadherin have effects on vascular permeability, which suggests that targeting VE-cadherin is feasible in controlling vascular barrier function. Further, blocking of VE-cadherin-mediated endothelial-cell adhesion affected microvessel stability.

Liao et al. were the first to reveal that BV13, a monoclonal antibody of VE-cadherin that binds to EC4, inhibits angiogenesis, tumor growth, and metastasis. However, administration of the monoclonal antibody (mAb) BV13 in vivo markedly increased permeability in the lungs and heart. To resolve this problem, another mAb, BV14, was developed; this did not significantly increase the permeability of the lungs, heart, and other organs, even after repeated high doses, and even in animals carrying well-developed tumors. BV14 and BV13 were equally effective in inhibiting angiogenesis in the mouse cornea and downregulating the growth of hemangioma and C6 glioma (Table 2). Corada et al. tested five different mAbs directed at different extracellular domains of VE-cadherin, to investigate their functions and side effects. They found that mAb Cad5, which binds to the EC1 domain of VE-cadherin, was the most effective in increasing permeability. EC1 may be important in mediating cell–cell interaction, and thus the binding of an antibody to it would disrupt the integrity of vessels. Another mAb, E4G10, binds to the N-terminal sequences of VE-cadherin; unlike BV13, which binds to all vasculature, E4G10 binds only to the tumor neovasculature. Therefore, future research should focus on finding ways to disrupt endothelial junctions in growing vessels, without affecting stabilized junctions in normal vessels. These findings demonstrate that VE-cadherin plays a crucial role in postnatal angiogenesis, and further validate VE-cadherin as a potential target for antiangiogenic treatment.

As with VE-cadherin, it has long been known that N-cadherin occurs on endothelial cells, but its role in vascular structure is only now becoming a focus of research. Inhibition of N-cadherin function destabilizes microvessels structure. For example, direct blockage of N-cadherin impedes the adhesive complex between endothelial cells and pericytes, and thus induces hemorrhage. Several types of antagonists targeting N-cadherin have been discovered. Three types of antagonists are based on the cell adhesion recognition sequence HAV: synthetic linear peptides, synthetic cyclic peptides, and non-peptidyl peptidomimetics. ADH-1, a synthetic cyclic peptide harboring the HAV motif, has been shown to inhibit angiogenesis in various model systems, including the chick chorioallantoic membrane assay. When ADH-1 is used in a tumor-bearing mouse model, the hemorrhage that it causes is limited to tumor blood vessels, without affecting normal vessels. Therefore, it is possible that the antiangiogenic properties of ADH-1 induced the massive apoptosis we observed in the tumors that we studied. Another N-cadherin antagonist, H-SWTLYTPSGQSK-NH 2, has recently been discovered; it may inhibit endothelial cell tube formation in vitro, indicating that it has antiangiogenic properties. In 2010, two monoclonal antibodies of N-cadherin were developed that inhibit the invasiveness and proliferation of N-cadherin-expressing cancer cells in vitro and suppress tumor growth and lymph-node metastasis in vivo.

Although VE-cadherin and N-cadherin are promising targets in tumor therapy, they have some shortcomings. Toxicity is one of the questions needed to be solved in the future, as they both widely expressed in normal tissues like vascular, heart, peripheral nerve and liver. Loss of VE-cadherin might cause hemorrhage and loss of N-cadherin can disrupt the structure of organs, leading to severe side effects. More precise targeting is high on the agenda, so do further preclinical and clinical testing to confirm the safety.

Blockade of Metastasis

As N-cadherin involves in cancer metastasis, N-cadherin antagonists are showing promise as therapeutic drugs for inhibiting cell adhesion and modulating cell signaling, thus preventing tumor metastasis. As mentioned above, ADH-1 is a stable cyclic peptide harboring an HAV motif, which similarly inhibited N-cadherin-dependent functioning. It has been reported that ADH-1 can cause apoptosis in several cancer cells and inhibit tumor cell migration at sub-cytotoxic concentrations. In a pre-clinical mouse model, ADH-1 not only inhibited primary tumor growth, but also prevented localized tumor invasion and metastasis. Further, ADH-1 has entered clinical testing, and there are two completed Phase I studies. Combination of ADH-1 and various cytotoxic agents has shown great promise: positive results in animal models, the absence of severe side effects, and promising antitumor effects in Phase I studies. There are also several monoclonal antibodies, such as GC4, directed against N-cadherin, that can block N-cadherin-dependent tumor migration and invasion in vitro and metastasis in vivo. Besides, GC-4-mediated blocking could increase the sensitivity to imatinib in CML, which means a potential therapeutic strategy in tyrosine kinase inhibitor resistance. 1H7 (targeting N-cadherin EC1–3) and 2A9 (targeting N-cadherin EC4) are newfound antibodies targeting N-cadherin and have been proved effectiveness in treating prostate cancer in mouse model. Both slowed down tumor growth and reduced local invasion and distant metastasis in lymph nodes.

OB-cadherin might also be effective as a therapeutic target. Kaur et al. found that OB-cadherin knockdown markedly reduced the survival ability of cancer cells in vitro and colony-forming abilities when there were no exogenous growth factors. Therefore, OB-cadherin is a potential target to reduce the aggressiveness and motility of cancer, and develop specific drugs to target it is an urgent priority. To explore this possibility, Lee et al. generated a panel of monoclonal antibodies (mAbs) against the OB-cadherin extracellular domain; one of these, mAb 2C7, inhibited the osseous metastasis of PC3-MM 2 cells (Table 2).

Taken together, cadherins targeted therapy could effectively limit the progression and angiogenesis of cancer, and further studies should be focused on elevating the specificity and effectiveness, as well as the combination therapies.

Conclusions

In summary, cadherins are key factors in maintaining normal tissue development. However, abnormal expression is found in tumorigenesis, development and metastasis. Therefore, a better understanding of cadherins is critical for cancer clinical applications, especially as therapeutic targets. In this review, we have discussed the various types of cadherins, their effects on tumor growth, and the clinical application of cadherins. Targeting cadherins is a promising strategy for cancer treatment and further studies and clinical experiments are needed to make it come true.

Author Contributions

WY and LY contributed equally to preparing and writing the manuscript. WY and TL prepared the figures and tables. LY and YZ designed, reviewed, and edited the manuscript.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Nieman MT Prudoff RS Johnson KR Wheelock MJ. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol. (1999 ) 147:631–44.

    Not in our library10.1083/jcb.147.3.631

  110. 110.

    Hazan RB Phillips GR Qiao RF Norton L Aaronson SA. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol. (2000 ) 148:779–90.

    Not in our library10.1083/jcb.148.4.779

  111. 111.

    Hulit J Suyama K Chung S Keren R Agiostratidou G Shan W. N-cadherin signaling potentiates mammary tumor metastasis via enhanced extracellular signal-regulated kinase activation. Cancer Res. (2007 ) 67:3106–16.

    Not in our library10.1158/0008-5472.can-06-3401

  112. 112.

    Takeichi M. Cadherins in cancer: implications for invasion and metastasis. Curr Opin Cell Biol. (1993 ) 5:806–11.

    Not in our library10.1016/0955-0674(93)90029-p

  113. 113.

    Pizarro A Gamallo C Benito N Palacios J Quintanilla M Cano A. Differential patterns of placental and epithelial cadherin expression in basal cell carcinoma and in the epidermis overlying tumours. Br J Cancer. (1995 ) 72:327–32.

    Not in our library10.1038/bjc.1995.333

  114. 114.

    Fujita M Furukawa F Fujii K Horiguchi Y Takeichi M Imamura S. Expression of cadherin cell adhesion molecules during human skin development: morphogenesis of epidermis, hair follicles and eccrine sweat ducts. Arch Dermatol Res. (1992 ) 284:159–66.

    Not in our library10.1007/bf00372710

  115. 115.

    Hibi K Goto T Mizukami H Kitamura YH Sakuraba K Sakata M Saito M. Demethylation of the CDH3 gene is frequently detected in advanced colorectal cancer. Anticancer Res. (2009 ) 29:2215–7.

    Not in our library

  116. 116.

    Hibi K Kitamura YH Mizukami H Goto T Sakuraba K Sakata M. Frequent CDH3 demethylation in advanced gastric carcinoma. Anticancer Res. (2009 ) 29:3945–7.

    Not in our library

  117. 117.

    Paredes J Albergaria A Oliveira JT Jeronimo C Milanezi F Schmitt FC. P-cadherin overexpression is an indicator of clinical outcome in invasive breast carcinomas and is associated with CDH3 promoter hypomethylation. Clin Cancer Res. (2005 ) 11:5869–77.

    Not in our library10.1158/1078-0432.ccr-05-0059

  118. 118.

    Xi Y Zhang X Yang Z Zhang X Guo Q Zhang Z. Prognositic significance of P-cadherin expression in breast cancer: protocol for a meta-analysis. Medicine (Baltimore). (2019 ) 98:e14924.

    Not in our library10.1097/md.0000000000014924

  119. 119.

    Mandeville JA Silva Neto B Vanni AJ Smith GL Rieger-Christ KM Zeheb R. P-cadherin as a prognostic indicator and a modulator of migratory behaviour in bladder carcinoma cells. BJU Int. (2008 ) 102:1707–14.

    Not in our library10.1111/j.1464-410x.2008.08115.x

  120. 120.

    Taniuchi K Nakagawa H Hosokawa M Nakamura T Eguchi H Ohigashi H. Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cancer cells by interacting with p120ctn and activating rho-family GTPases. Cancer Res. (2005 ) 65:3092–9.

    Not in our library10.1158/0008.5472.can-04-3646

  121. 121.

    Sun L Hu H Peng L Zhou Z Zhao X Pan J. P-cadherin promotes liver metastasis and is associated with poor prognosis in colon cancer. Am J Pathol. (2011 ) 179:380–90.

    Not in our library10.1016/j.ajpath.2011.03.046

  122. 122.

    Pishvaian MJ Feltes CM Thompson P Bussemakers MJ Schalken JA Byers SW. Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Res. (1999 ) 59:947–52.

    Not in our library

  123. 123.

    Satriyo PB Bamodu OA Chen JH Aryandono T Haryana SM Yeh CT. Cadherin 11 inhibition downregulates β-catenin, deactivates the canonical WNT signalling pathway and suppresses the cancer stem cell-like phenotype of triple negative breast cancer. J Clin Med. (2019 ) 8:E148.

    Not in our library10.3390/jcm8020148

  124. 124.

    Bartolome RA Torres S Isern de Val S Escudero-Paniagua B Calvino E Teixido J. VE-cadherin RGD motifs promote metastasis and constitute a potential therapeutic target in melanoma and breast cancers. Oncotarget. (2017 ) 8:215–27.

    Not in our library10.18632/oncotarget.13832

  125. 125.

    Shan M Su Y Kang W Gao R Li X Zhang G. Aberrant expression and functions of protocadherins in human malignant tumors. Tumour Biol. (2016 ) 37:12969–81.

    Not in our library10.1007/s13277-016-5169-9

  126. 126.

    Asad M Wong MK Tan TZ Choolani M Low J Mori S. FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway. Cell Death Dis. (2014 ) 5:e1346.

    Not in our library10.1038/cddis.2014.302

  127. 127.

    Wang C Tao B Li S Li B Wang X Hu G. Characterizing the role of PCDH9 in the regulation of glioma cell apoptosis and invasion. J Mol Neurosci. (2014 ) 52:250–60.

    Not in our library10.1007/s12031-013-0133-2

  128. 128.

    Chen T Long B Ren G Xiang T Li L Wang Z. Protocadherin20 acts as a tumor suppressor gene: epigenetic inactivation in nasopharyngeal carcinoma. J Cell Biochem. (2015 ) 116:1766–75.

    Not in our library10.1002/jcb.25135

  129. 129.

    Wu JC Wang FZ Tsai ML Lo CY Badmaev V Ho CT. Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells. Mol Nutr Food Res. (2015 ) 59:2511–22.

    Not in our library10.1002/mnfr.201500373

  130. 130.

    Dang Z Shangguan J Zhang C Hu P Ren Y Lv Z. Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma. Tumour Biol. (2016 ) 37:2527–35.

    Not in our library10.1007/s13277-015-3970-5

  131. 131.

    Xu Y Yang Z Yuan H Li Z Li Y Liu Q. PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway. Oncol Rep. (2015 ) 34:747–54.

    Not in our library10.3892/or.2015.4056

  132. 132.

    Jao TM Tsai MH Lio HY Weng WT Chen CC Tzeng ST. Protocadherin 10 suppresses tumorigenesis and metastasis in colorectal cancer and its genetic loss predicts adverse prognosis. Int J Cancer. (2014 ) 135:2593–603.

    Not in our library10.1002/ijc.28899

  133. 133.

    Bos PD Zhang XH Nadal C Shu W Gomis RR Nguyen DX. Genes that mediate breast cancer metastasis to the brain. Nature. (2009 ) 459:1005–9.

    Not in our library10.1038/nature08021

  134. 134.

    Chen MW Vacherot F De La Taille A Gil-Diez-De-Medina S Shen R Friedman RA. The emergence of protocadherin-PC expression during the acquisition of apoptosis-resistance by prostate cancer cells. Oncogene. (2002 ) 21:7861–71.

    Not in our library10.1038/sj.onc.1205991

  135. 135.

    Terry S Maille P Baaddi H Kheuang L Soyeux P Nicolaiew N. Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. Neoplasia. (2013 ) 15:761–72.

    Not in our library10.1593/neo.122070

  136. 136.

    Viallard C Larrivee B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. (2017 ) 20:409–26.

    Not in our library10.1007/s10456-017-9562-9

  137. 137.

    Wu JB Tang YL Liang XH. Targeting VEGF pathway to normalize the vasculature: an emerging insight in cancer therapy. Onco Targets Ther. (2018 ) 11:6901–9.

    Not in our library10.2147/ott.s172042

  138. 138.

    Suzuki S Sano K Tanihara H. Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue. Cell Regul. (1991 ) 2:261–70.

    Not in our library10.1091/mbc.2.4.261

  139. 139.

    Gory-Faure S Prandini MH Pointu H Roullot V Pignot-Paintrand I Vernet M. Role of vascular endothelial-cadherin in vascular morphogenesis. Development. (1999 ) 126:2093–102.

    Not in our library10.1242/dev.126.10.2093

  140. 140.

    Kouklis P Konstantoulaki M Malik AB. VE-cadherin-induced Cdc42 signaling regulates formation of membrane protrusions in endothelial cells. J Biol Chem. (2003 ) 278:16230–6.

    Not in our library10.1074/jbc.m212591200

  141. 141.

    Breviario F Caveda L Corada M Martin-Padura I Navarro P Golay J. Functional properties of human vascular endothelial cadherin (7B4/cadherin-5), an endothelium-specific cadherin. Arterioscler Thromb Vasc Biol. (1995 ) 15:1229–39.

    Not in our library10.1161/01.atv.15.8.1229

  142. 142.

    Zhang R Li R Tang Y. Soluble vascular endothelial cadherin: a promising marker of critical illness? Crit Care. (2019 ) 23:57.

    Not in our library10.1186/s13054-019-2343-7

  143. 143.

    Wallez Y Vilgrain I Huber P. Angiogenesis: the VE-cadherin switch. Trends Cardiovasc Med. (2006 ) 16:55–9.

    Not in our library10.1016/j.tcm.2005.11.008

  144. 144.

    Labelle M Schnittler HJ Aust DE Friedrich K Baretton G Vestweber D. Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor beta signaling. Cancer Res. (2008 ) 68:1388–97.

    Not in our library10.1158/0008-5472.can-07-2706

  145. 145.

    Dejana E Orsenigo F Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. (2008 ) 121:2115–22.

    Not in our library10.1242/jcs.017897

  146. 146.

    Weis S Shintani S Weber A Kirchmair R Wood M Cravens A. Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction. J Clin Invest. (2004 ) 113:885–94.

    Not in our library10.1172/jci200420702

  147. 147.

    Eliceiri BP Paul R Schwartzberg PL Hood JD Leng J Cheresh DA. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell. (1999 ) 4:915–24.

    Not in our library10.1016/s1097-2765(00)80221-x

  148. 148.

    Grazia Lampugnani M Zanetti A Corada M Takahashi T Balconi G Breviario F. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148. J Cell Biol. (2003 ) 161:793–804.

    Not in our library10.1083/jcb.200209019

  149. 149.

    Rudini N Felici A Giampietro C Lampugnani M Corada M Swirsding K. VE-cadherin is a critical endothelial regulator of TGF-beta signalling. EMBO J. (2008 ) 27:993–1004.

    Not in our library10.1038/emboj.2008.46

  150. 150.

    Hou WH Liu IH Tsai CC Johnson FE Huang SS Huang JS. CRSBP-1/LYVE-1 ligands disrupt lymphatic intercellular adhesion by inducing tyrosine phosphorylation and internalization of VE-cadherin. J Cell Sci. (2011 ) 124:1231–44.

    Not in our library10.1242/jcs.078154

  151. 151.

    Giampietro C Taddei A Corada M Sarra-Ferraris GM Alcalay M Cavallaro U. Overlapping and divergent signaling pathways of N-cadherin and VE-cadherin in endothelial cells. Blood. (2012 ) 119:2159–70.

    Not in our library10.1182/blood-2011-09-381012

  152. 152.

    Gerhardt H Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res. (2003 ) 314:15–23.

    Not in our library10.1007/s00441-003-0745-x

  153. 153.
    Tumor endothelial cell-derived cadherin-2 promotes angiogenesis and has prognostic significance for lung adenocarcinoma · 2019
    Not checked
  154. 154.

    Gerhardt H Wolburg H Redies C. N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn. (2000 ) 218:472–9.

    Not in our library10.1002/1097-0177(200007)218:3<472::aid-dvdy1008>3.0.co;2-#

  155. 155.

    Luo Y Radice GL. N-cadherin acts upstream of VE-cadherin in controlling vascular morphogenesis. J Cell Biol. (2005 ) 169:29–34.

    Not in our library10.1083/jcb.200411127

  156. 156.

    Nalla AK Estes N Patel J Rao JS. N-cadherin mediates angiogenesis by regulating monocyte chemoattractant protein-1 expression via PI3K/Akt signaling in prostate cancer cells. Exp Cell Res. (2011 ) 317:2512–21.

    Not in our library10.1016/j.yexcr.2011.07.024

  157. 157.

    Viollet C Doherty P. CAMs and the FGF receptor: an interacting role in axonal growth. Cell Tissue Res. (1997 ) 290:451–5.

    Not in our library10.1007/s004410050952

  158. 158.

    Saffell JL Williams EJ Mason IJ Walsh FS Doherty P. Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. Neuron. (1997 ) 18:231–42.

    Not in our library10.1016/s0896-6273(00)80264-0

  159. 159.

    Derycke L Morbidelli L Ziche M De Wever O Bracke M Van Aken E. Soluble N-cadherin fragment promotes angiogenesis. Clin Exp Metastasis. (2006 ) 23:187–201.

    Not in our library10.1007/s10585-006-9029-7

  160. 160.

    Fridman WH Dieu-Nosjean MC Pages F Cremer I Damotte D Sautes-Fridman C. The immune microenvironment of human tumors: general significance and clinical impact. Cancer Microenviron. (2013 ) 6:117–22.

    Not in our library10.1007/s12307-012-0124-9

  161. 161.

    Van den Bossche J Malissen B Mantovani A De Baetselier P Van Ginderachter JA. Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs. Blood. (2012 ) 119:1623–33.

    Not in our library10.1182/blood-2011-10-384289

  162. 162.

    Nawijn MC Hackett TL Postma DS van Oosterhout AJ Heijink IH. E-cadherin: gatekeeper of airway mucosa and allergic sensitization. Trends Immunol. (2011 ) 32:248–55.

    Not in our library10.1016/j.it.2011.03.004

  163. 163.

    Jiang Y Wan T Chen G Xiu F Xia D Zhang W. DC-CLM, a cadherin-like molecule cloned from human dendritic cells, inhibits growth of breast cancer cells. J Cancer Res Clin Oncol. (2003 ) 129:57–64.

    Not in our library10.1007/s00432-002-0404-8

  164. 164.

    Riedl E Stockl J Majdic O Scheinecker C Knapp W Strobl H. Ligation of E-cadherin on in vitro-generated immature Langerhans-type dendritic cells inhibits their maturation. Blood. (2000 ) 96:4276–84.

    Not in our library

  165. 165.

    Padovan E Terracciano L Certa U Jacobs B Reschner A Bolli M. Interferon stimulated gene 15 constitutively produced by melanoma cells induces E-cadherin expression on human dendritic cells. Cancer Res. (2002 ) 62:3453–8.

    Not in our library

  166. 166.

    Jiang A Bloom O Ono S Cui W Unternaehrer J Jiang S. Disruption of E-cadherin-mediated adhesion induces a functionally distinct pathway of dendritic cell maturation. Immunity. (2007 ) 27:610–24.

    Not in our library10.1016/j.immuni.2007.08.015

  167. 167.

    Manicassamy S Reizis B Ravindran R Nakaya H Salazar-Gonzalez RM Wang YC. Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science. (2010 ) 329:849–53.

    Not in our library10.1126/science.1188510

  168. 168.

    Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. (2009 ) 9:259–70.

    Not in our library10.1038/nri2528

  169. 169.

    Rehli M Sulzbacher S Pape S Ravasi T Wells CA Heinz S. Transcription factor Tfec contributes to the IL-4-inducible expression of a small group of genes in mouse macrophages including the granulocyte colony-stimulating factor receptor. J Immunol. (2005 ) 174:7111–22.

    Not in our library10.4049/jimmunol.174.11.7111

  170. 170.

    Ghassabeh GH De Baetselier P Brys L Noel W Van Ginderachter JA Meerschaut S. Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood. (2006 ) 108:575–83.

    Not in our library10.1182/blood-2005-04-1485

  171. 171.

    Wanat KA Rosenbach M Zoiber AF Zhang PJ Schaffer A. E-cadherin is expressed by mono- and multinucleated histiocytes in cutaneous sarcoidal and foreign body granulomas. Am J Dermatopathol. (2014 ) 36:651–4.

    Not in our library10.1097/dad.0b013e31828de7e0

  172. 172.

    Van den Bossche J Bogaert P van Hengel J Guerin CJ Berx G Movahedi K. Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes. Blood. (2009 ) 114:4664–74.

    Not in our library10.1182/blood-2009-05-221598

  173. 173.

    Van den Bossche J Laoui D Naessens T Smits HH Hokke CH Stijlemans B E-cadherin expression in macrophages dampens their inflammatory responsiveness in vitro, but does not modulate M2-regulated pathologies in vivo. Sci Rep. (2015 ) 5:12599

    Not in our library10.1038/srep12599

  174. 174.

    Movahedi K Laoui D Gysemans C Baeten M Stange G Van den Bossche J. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. (2010 ) 70:5728–39.

    Not in our library10.1158/0008-5472.can-09-4672

  175. 175.

    Schietke R Warnecke C Wacker I Schodel J Mole DR Campean V. The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. J Biol Chem. (2010 ) 285:6658–69.

    Not in our library10.1074/jbc.m109.042424

  176. 176.

    Moreno JL Mikhailenko I Tondravi MM Keegan AD. IL-4 promotes the formation of multinucleated giant cells from macrophage precursors by a STAT6-dependent, homotypic mechanism: contribution of E-cadherin. J Leukoc Biol. (2007 ) 82:1542–53.

    Not in our library10.1189/jlb.0107058

  177. 177.

    Schaale K Neumann J Schneider D Ehlers S Reiling N. Wnt signaling in macrophages: augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur J Cell Biol. (2011 ) 90:553–9.

    Not in our library10.1016/j.ejcb.2010.11.004

  178. 178.

    Li Y Hofmann M Wang Q Teng L Chlewicki LK Pircher H. Structure of natural killer cell receptor KLRG1 bound to E-cadherin reveals basis for MHC-independent missing self recognition. Immunity. (2009 ) 31:35–46.

    Not in our library10.1016/j.immuni.2009.04.019

  179. 179.

    Ito M Maruyama T Saito N Koganei S Yamamoto K Matsumoto N. Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med. (2006 ) 203:289–95.

    Not in our library10.1084/jem.20051986

  180. 180.

    Robbins SH Nguyen KB Takahashi N Mikayama T Biron CA Brossay L. Cutting edge: inhibitory functions of the killer cell lectin-like receptor G1 molecule during the activation of mouse NK cells. J Immunol. (2002 ) 168:2585–9.

    Not in our library10.4049/jimmunol.168.6.2585

  181. 181.

    Robbins SH Terrizzi SC Sydora BC Mikayama T Brossay L. Differential regulation of killer cell lectin-like receptor G1 expression on T cells. J Immunol. (2003 ) 170:5876–85.

    Not in our library10.4049/jimmunol.170.12.5876

  182. 182.

    Beyersdorf N Ding X Tietze JK Hanke T. Characterization of mouse CD4 T cell subsets defined by expression of KLRG1. Eur J Immunol. (2007 ) 37:3445–54.

    Not in our library10.1002/eji.200737126

  183. 183.

    Cepek KL Shaw SK Parker CM Russell GJ Morrow JS Rimm DL. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature. (1994 ) 372:190–3.

    Not in our library10.1038/372190a0

  184. 184.

    Yu Y Feng XH. TGF-beta signaling in cell fate control and cancer. Curr Opin Cell Biol. (2019 ) 61:56–63.

    Not in our library10.1016/j.ceb.2019.07.007

  185. 185.
    Targeting PI3K in cancer: mechanisms and advances in clinical trials · 2019
    No notice
  186. 186.

    Galluzzi L Spranger S Fuchs E Lopez-Soto A. WNT signaling in cancer immunosurveillance. Trends Cell Biol. (2019 ) 29:44–65.

    Not in our library10.1016/j.tcb.2018.08.005

  187. 187.

    Olgen S. Overview on anticancer drug design and development. Curr Med Chem. (2018 ) 25:1704–19.

    Not in our library10.2174/0929867325666171129215610

  188. 188.

    Kumar B Singh S Skvortsova I Kumar V. Promising targets in anti-cancer drug development: recent updates. Curr Med Chem. (2017 ) 24:4729–52.

    Not in our library10.2174/0929867324666170331123648

  189. 189.

    Zajac M Muszalska I Jelinska A. New molecular targets of anticancer therapy - current status and perspectives. Curr Med Chem. (2016 ) 23:4176–220.

    Not in our library10.2174/0929867323666160814002150

  190. 190.

    Wilson CW Ye W. Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling. Cell Adhes Migr. (2014 ) 8:76–83.

    Not in our library10.4161/cam.28115

  191. 191.

    May C Doody JF Abdullah R Balderes P Xu X Chen CP. Identification of a transiently exposed VE-cadherin epitope that allows for specific targeting of an antibody to the tumor neovasculature. Blood. (2005 ) 105:4337–44.

    Not in our library10.1182/blood-2005-01-0010

  192. 192.

    Corada M Zanetta L Orsenigo F Breviario F Lampugnani MG Bernasconi S. A monoclonal antibody to vascular endothelial-cadherin inhibits tumor angiogenesis without side effects on endothelial permeability. Blood. (2002 ) 100:905–11.

    Not in our library10.1182/blood.v100.3.905

  193. 193.

    Liao F Li Y O'Connor W Zanetta L Bassi R Santiago A. Monoclonal antibody to vascular endothelial-cadherin is a potent inhibitor of angiogenesis, tumor growth, and metastasis. Cancer Res. (2000 ) 60:6805–10.

    Not in our library

  194. 194.

    Corada M Mariotti M Thurston G Smith K Kunkel R Brockhaus M. Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc Natl Acad Sci USA. (1999 ) 96:9815–20.

    Not in our library10.1073/pnas.96.17.9815

  195. 195.

    Liao F Doody JF Overholser J Finnerty B Bassi R Wu Y. Selective targeting of angiogenic tumor vasculature by vascular endothelial-cadherin antibody inhibits tumor growth without affecting vascular permeability. Cancer Res. (2002 ) 62:2567–75.

    Not in our library

  196. 196.

    Devemy E Blaschuk OW. Identification of a novel N-cadherin antagonist. Peptides. (2008 ) 29:1853–61.

    Not in our library10.1016/j.peptides.2008.06.025

  197. 197.

    Williams E Williams G Gour BJ Blaschuk OW Doherty P. A novel family of cyclic peptide antagonists suggests that N-cadherin specificity is determined by amino acids that flank the HAV motif. J Biol Chem. (2000 ) 275:4007–12.

    Not in our library10.1074/jbc.275.6.4007

  198. 198.

    Blaschuk OW. N-cadherin antagonists as oncology therapeutics. Philos Trans R Soc Lond B Biol Sci. (2015 ) 370:20140039.

    Not in our library10.1098/rstb.2014.0039

  199. 199.

    Harrison OJ Corps EM Berge T Kilshaw PJ. The mechanism of cell adhesion by classical cadherins: the role of domain 1. J Cell Sci. (2005 ) 118:711–21.

    Not in our library10.1242/jcs.01665

  200. 200.

    Tanaka H Kono E Tran CP Miyazaki H Yamashiro J Shimomura T. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med. (2010 ) 16:1414–20.

    Not in our library10.1038/nm.2236

  201. 201.

    Lee YC Bilen MA Yu G Lin SC Huang CF Ortiz A. Inhibition of cell adhesion by a cadherin-11 antibody thwarts bone metastasis. Mol Cancer Res. (2013 ) 11:1401–11.

    Not in our library10.1158/1541-7786.mcr-13-0108

  202. 202.

    Corada M Liao F Lindgren M Lampugnani MG Breviario F Frank R. Monoclonal antibodies directed to different regions of vascular endothelial cadherin extracellular domain affect adhesion and clustering of the protein and modulate endothelial permeability. Blood. (2001 ) 97:1679–84.

    Not in our library10.1182/blood.v97.6.1679

  203. 203.

    Burg N Swendeman S Worgall S Hla T Salmon JE. Sphingosine 1-phosphate receptor 1 signaling maintains endothelial cell barrier function and protects against immune complex-induced vascular injury. Arthritis Rheumatol. (2018 ) 70:1879–89.

    Not in our library10.1002/art.40558

  204. 204.

    Blaschuk OW. Discovery and development of N-cadherin antagonists. Cell Tissue Res. (2012 ) 348:309–13.

    Not in our library10.1007/s00441-011-1320-5

  205. 205.

    Blaschuk OW Sullivan R David S Pouliot Y. Identification of a cadherin cell adhesion recognition sequence. Dev Biol. (1990 ) 139:227–9.

    Not in our library10.1016/0012-1606(90)90290-y

  206. 206.

    Sadler NM Harris BR Metzger BA Kirshner J. N-cadherin impedes proliferation of the multiple myeloma cancer stem cells. Am J Blood Res. (2013 ) 3:271–85.

    Not in our library

  207. 207.

    Lammens T Swerts K Derycke L De Craemer A De Brouwer S De Preter K. N-cadherin in neuroblastoma disease: expression and clinical significance. PLoS ONE. (2012 ) 7:e31206.

    Not in our library10.1371/journal.pone.0031206

  208. 208.

    Kelland L. Drug evaluation: ADH-1, an N-cadherin antagonist targeting cancer vascularization. Curr Opin Mol Ther. (2007 ) 9:86–91.

    Not in our library

  209. 209.

    Erez N Zamir E Gour BJ Blaschuk OW Geiger B. Induction of apoptosis in cultured endothelial cells by a cadherin antagonist peptide: involvement of fibroblast growth factor receptor-mediated signalling. Exp Cell Res. (2004 ) 294:366–78.

    Not in our library10.1016/j.yexcr.2003.11.033

  210. 210.

    Mrozik KM Cheong CM Hewett D Chow AW Blaschuk OW Zannettino AC. Therapeutic targeting of N-cadherin is an effective treatment for multiple myeloma. Br J Haematol. (2015 ) 171:387–99.

    Not in our library10.1111/bjh.13596

  211. 211.

    Mariotti A Perotti A Sessa C Ruegg C. N-cadherin as a therapeutic target in cancer. Expert Opin Investig Drugs. (2007 ) 16:451–65.

    Not in our library10.1517/13543784.16.4.451

  212. 212.

    Groen RW de Rooij MF Kocemba KA Reijmers RM de Haan-Kramer A Overdijk MB. N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. Haematologica. (2011 ) 96:1653–61.

    Not in our library10.3324/haematol.2010.038133

  213. 213.

    Volk T Volberg T Sabanay I Geiger B. Cleavage of A-CAM by endogenous proteinases in cultured lens cells and in developing chick embryos. Dev Biol. (1990 ) 139:314–26.

    Not in our library10.1016/0012-1606(90)90301-x

  214. 214.

    Eiring AM Khorashad JS Anderson DJ Yu F Redwine HM Mason CC β-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia. (2015 ) 29:2328–37.

    Not in our library10.1038/leu.2015.196

  215. 215.

    Gao Y Qu Y Zhou Q Ma Y. SIRT6 inhibits proliferation and invasion in osteosarcoma cells by targeting N-cadherin. Oncol Lett. (2019 ) 17:1237–44.

    Not in our library10.3892/ol.2018.9676

  216. 216.

    Kaur H Phillips-Mason PJ Burden-Gulley SM Kerstetter-Fogle AE Basilion JP Sloan AE. Cadherin-11, a marker of the mesenchymal phenotype, regulates glioblastoma cell migration and survival in vivo. Mol Cancer Res. (2012 ) 10:293–304.

    Not in our library10.1158/1541-7786.mcr-11-0457

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