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Review

Role of Cadherins in Cancer—A Review

1
Department of Small Animal Diseases, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
2
Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
3
Carnivore Reproduction Study Center, Ecole Nationale Veterinaire d’Alfort, 94700 Maison Alfort, France
4
Department of Preclinical Sciences, Institute of Veterinary Medicine; Warsaw University of Life Sciences, 02-787 Warsaw, Poland
5
Center for Integrative Mammalian Research, Ross University School of Veterinary Medicine, BOX 334 Basseterre, Saint Kitts and Nevis, West Indies
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207624
Submission received: 17 August 2020 / Revised: 10 October 2020 / Accepted: 12 October 2020 / Published: 15 October 2020
(This article belongs to the Special Issue Activations of Cadherin Signaling in Cancer)

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 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.

1. Introduction

Cadherins are transmembrane glycoproteins responsible for cell-cell adhesion and maintenance of normal tissue architecture. In addition, cadherins have been found not only between the tumor cells but also in body fluids (mainly in blood) [1,2,3]. The classical cadherins, among which there are many subgroups, are a class of adhesion molecules that interact with catenins through the cytoplasmic domain [1]. The classical cadherins are epithelial-cadherin, placental-cadherin and neural-cadherin (E-, P- and N-cadherin, respectively).
The structure of cadherin is well known and has been extensively reviewed by others [2,3,4,5]. Briefly, the extracellular part of classical cadherin is built of five extracellular cadherin domains (ECs). There are at least 20 subtypes of the classical cadherin encoded in the mammalian genome, and all of them are similarly organized as the 5-EC structure. The five cadherins mediate Ca-dependent adhesion via their extracellular domains provide homotypic cell-cell interactions, and a cytoplasmic tail binds to several adaptor molecules to transmit physical and biochemical signals to the cell [6]. The frequent cytoplasmic binding partner is β-catenin but certain cadherins may also bind the plakoglobin [7]. Cadherins extracellular domains join with cytoplasmic tail to form signaling hubs called adherens junctions (AJs). Through AJs, cadherin interacts with cadherin on the adjacent cells, forming a zipper-like structure. The AJs connect the actin cytoskeleton of neighboring cells through direct interaction. Besides maintenance of tissue architecture, crucial stages of embryogenesis such as formation of the gastrula, neurula and organogenesis rely on the expression of cadherin. Moreover, progesterone with endometrial calcitonin regulates the expression of cadherin, which has an impact on endometrial tissue compactness and embryo implantation [8]. Later, in mature tissues, cadherins are responsible for the maintenance of cell polarity, tissue integrity and homeostasis [9]. However, during carcinogenesis, cadherins are often inactivated or functionally blocked, allowing the development and progression of cancer or the metastatic processes [6].
The role of cadherins in the process of cancer development has been studied widely over the last decades [6,10,11,12]. In human medicine, cadherins have been evaluated in many malignancies, such as pancreatic cancer, melanoma, hepatocellular carcinoma, glioblastoma, breast and gastric cancers [13,14,15,16]. Because most of humans’ solid tumors are of epithelial origin, adhesion molecules at the junctions of epithelial cells and cell signaling pathways are of great interest. Many studies have described E-cadherin function as a tumor suppressor [17,18,19]. However, recent studies have shown that E-cadherin, especially in late-stage cancers, may also promote cell migration, invasion and even tumor progression [20,21,22,23,24]. Genetic deficits in E-cadherin cell surface regulation may contribute to cancer development [25]. Some studies have described a process which occurs during metastatic colonization named mesenchymal-to-epithelial transition (MET), in which E-cadherin is re-expressed [26]. E-cadherin has also been shown to promote metastasis in diverse models of invasive ductal carcinomas [27]. Overexpression of N and P-cadherin in breast cancer patients is also a common finding, and it is usually related to poor prognosis [10]. The detailed role of N and P-cadherins will be discussed in further paragraphs.
The purpose of this review is to discuss the role of cadherins in the tumor growth and its clinical importance.

2. Cadherin-Catenin Complex

Cadherins preferentially bind to catenin proteins that are found in three subtypes, α-catenins, β-catenins, and p120ctn family catenins. A juxtamembrane region of cadherins, which is proximal to the cell membrane, binds to p120ctns, while the distal region called catenin-binding domain binds to β-catenins. Monomeric forms of α-catenins associate with the cadherin-catenin complex through β-catenins, while homodimeric forms of α-catenins do not bind β-catenins, but F-actin [28]. The connection between the cadherin and catenins has been referred as the cadherin-catenin complex. Cadherins, through their highly conserved cytoplasmic domains, bind to catenins; thus, they mediate biochemical signals (Figure 1). Specifically, the juxtamembrane domain of cadherin cytoplasmic tail binds to a family of proteins, including p120 catenin (p120; CTNND1), neural plakophilin-related armadillo protein (NPRAP/δ-catenin; CTNND2), armadillo repeat protein deleted in velo-cardio-facial syndrome (ARVCF) and plakophilin 4 (p0071). This connection is essential for the stabilization and function of the classical cadherin binding though other proteins to microtubules and kinesins, which regulates cadherin localization. As mentioned before, cadherins also often bind to β-catenin (CTNNB1) through the catenin-binding domain, which is located at the distal region of cadherin cytoplasmic tail. The interaction between β-catenin and the cytoplasmic domain of cadherin enables clustering into junctional structures. Any dysfunction of the cadherin-catenin complex reduces cell adhesion. Such dysfunction of the cadherin-β-catenin complex was seen in the neoplastic process leading to β-catenin accumulation in the cytoplasm and nucleus of the tumor cells. The function of β -catenin is equally important, because its association with cadherin links the Ajs to filamentous actin and promotes the re-organization of the actin cytoskeleton. Catenins mediate many signaling processes, which functionally connect cadherin-catenin complex to the cytoskeleton. Thus, they control the balance between cell-cell adhesion and cell differentiation, and regulate cell growth and motility [17]. The cadherin-catenin complexes are crucial for the ability of the cells to adhere to each other.

3. Cadherin and Catenin Signaling in Cancer

Cadherins, together with catenins, interact through the AJs with actin cytoskeleton and regulate cellular processes during embryonic development as well as during neoplastic transformation and progression. In cancer, any disturbances in cell-cell and cell-matrix adhesion are related to tumor progression and allow cancer cells to become more motile, degrade the extracellular matrix, enter the blood vessels and form distant metastases [9,30].
The signaling activation takes place at the site of cadherin-catenin interaction. Thus, the catenin-binding domain of cadherin is crucial in cadherin function and it plays an important role in maintaining epithelial integrity. For example, phosphorylation of either E-cadherin or β-catenin affects β-catenin binding to cadherin, while phosphorylation of β-catenin may also lead to α-catenin binding to the cadherin-β-catenin complex [17]. During tumorigenesis, due to the phosphorylation, β-catenin is released into the cytoplasm (also as a consequence of E-cadherin loss) and communicates with a protein complex composed of Axin, adenomatous polyposis coli (APC) and the Ser/Thr kinase glycogen synthase 3β (GSK-3β) [17,31]. The phosphorylation of β-catenin is induced by GSK-3 β as well as casein kinases I and II and leads to ubiquitination and subsequent degradation in the 26S proteasome. The E-Cadherin/β-catenin complex also affects the Wnt-signaling pathway (the vertebrate homolog of Wingless). Phosphorylated β-catenin enters in the degradation pathways unless WNT signaling is activated. β-catenin is considered the prime signal transducer of canonical Wnt pathway. Wnt pathway activation contributes to translocation of intact β-catenin to the nucleus, where, together with the lymphoid enhancer factor (LEF)/T-cell factor (TCF), it activates a variety of transcription factors, increasing transcription of target genes, such as Fz, LRP6, Axin2, Naked, Dkk1, and Rspo, resulting in positive or negative regulation by TCF/β-catenin [17,29,32,33,34,35,36,37]. Therefore, tyrosine phosphorylation of β-catenin leads to beta-catenin signaling activation (and transcriptional impact), whereas β-catenin degradation inhibition in the presence of Wnt signaling is an inactivating mechanism.
Furthermore, p120-catenin, which interacts with the cadherins through the juxtamembrane domain is regulated by tyrosine kinases and modulate cadherin intracellular trafficking, stability, adhesive capacity and motility [29]. p120 can be phosphorylated at multiple serine, threonine and tyrosine residues. The phosphorylation at many tyrosine sites (Y) is mediated by Src family kinases within its N-terminus, including Y96, Y112, Y228, Y257, Y280, Y291, Y296 and Y302. The p120 phosphorylation at serine/threonine sites regulates E-cadherin expression at the cell membrane, while p120 phosphorylation of tyrosine and serine sites influences on the strength of cadherin activation and adhesion [38]. p120-catenin may also influence cell adhesion by modulating the organization of actin cytoskeleton by activation of RhoA [29]. Many processes, including intracellular signaling pathways such as Wnt, transforming growth factor β (TGF-β), mitogen activated kinase (MAPK), gene transcription, protein stability and posttranslational modifications, can affect cell adhesion [29]. For example, TGF-β is a growth inhibitor of many cell types and E-cadherin enhances TGF-β signaling, and therefore, suppresses uncontrolled cell proliferation [39]. E-cadherin also activates MAPK signaling through epidermal growth factor receptors activation [40]. MAPK is an important signaling pathway, as it controls cell proliferation, differentiation and survival. Changes in the cell adhesion are important for tissue morphogenesis and repair processes but may also be related to tumor development. There are many oncogenic signaling pathways related to cadherin cell-cell adhesion. Among them are cyclin kinase inhibitor p27-mediated, phosphatidylinositol-3 kinase (PI3K)/AKT and ras-related C3 botulinum toxin substrate (Rac1) signaling, rat sarcoma viral oncogene (Ras), MAPK, as well as Hippo signaling [41,42,43,44]. For example, E-cadherin can increase the stability of cyclin-dependent kinase inhibitor p27, thereby upregulating p27 expression and inhibiting proliferation. Therefore, E-cadherin is also considered a growth suppressor [41,43]. Signaling by class 1 PI3-kinases is activated in response to various extracellular stimuli [45]. Such cadherin-activated PI3-kinase signaling has an impact on cadherin function and strength of cell-cell adhesion. E-cadherin mediated cell adhesion formation of tight junctions and apical polarity complexes leads to the Hippo signaling pathway activation. This pathway may be inhibited by mechanical stress; however, increased inhibition upon cell contact may be triggered by its activation [46]. However, the most common pathway of tumor development and progression is the nuclear β-catenin/T-cell factor (TCF) signaling pathway [17]. The cadherin-catenin complex can act both as a potentiator and attenuator of Wnt/β-catenin signaling [47]. In the first instance, cadherin-based cell-cell adhesion could increase the amino-terminal phosphorylation of β-catenin and its subsequent rate of destruction. In the second instance, cadherin-catenin complex is required for Wnt/β-catenin signaling, as it recruits kinases needed for the execution of canonical Wnt signals [47]. All these various mechanisms and the loss of anti-tumorigenic E-cadherin signaling, together with the presence of nuclear catenin signaling and the activation of various additional pathways (RTK, RhoGTPase), are main events related to tumor progression.
Many studies have shown the role of β-catenin as a proto-oncogene in human cancer [17,31]. Mutations in the gene CTNNB1 that encodes β-catenin have resulted in cancer. It is estimated that at least 10% of cancer samples sequenced have exhibited mutation in CTNNB1 [48]. These mutations were mostly located in the N-terminal region of β-catenin, β:TrCP binding motif. Damage to this binding motif disables ubiquitination and degradation of β-catenin. As such, stabilized β-catenin accumulates in the cytoplasm and then is translocated to the nucleus, where it concomitantly drives transcription of its target genes [49]. Apart from its role in tumor progression, the nuclear signaling pathway of β-catenin is responsible for the pluripotent phenotype and self-renewal of both normal and cancer stem cells [17,41,49].

4. Epithelial Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a pivotal process of morphogenesis whereby epithelial cells acquire the mesenchymal phenotype. EMT is known as the phenomenon of loss of E-cadherin expression during cancer progression [50]. EMT occurs during embryonic development processes such as gastrulation, neural crest development and placenta formation. Because EMT is an essential hallmark in embryogenesis, scientists postulated the idea that epithelial cancers must acquire mesenchymal characteristics for invasion and metastasis [51,52].
In carcinomas, EMT can be initiated and promoted by many oncogenic signaling pathways, including hypoxia and signals of the tumor microenvironment (Figure 2). Subsequently, this leads to epithelial cells losing their cell polarity and cell–cell adhesion, thus gaining the migratory and invasive properties [50]. In breast cancer, a “cadherin-switch” is defined as above-mentioned loss of E-cadherin and increased expression of N-cadherin during tumor progression [53]. This transition induces or enhances the metastatic capacity of the carcinoma cells. There are many identified mechanisms of E-cadherin mediated tumor suppression [54,55,56]. The mechanism of tumor suppression may come from the adhesive function of E-cadherin, which prevents tumor cells from dissociating from one another, and therefore, prevents their migration to other tissues. The alternative mechanism of tumor suppression is via antagonizing the nuclear signaling function of β-catenin and altering its ability to regulate target genes that support tumor invasion, as β-catenin is a proto-oncogene [54]. It was shown that only E-cadherin constructs that had β-catenin binding were able to retain the tumor growth and not E-cadherin constructs that exhibited adhesive activity without β-catenin binding. In addition, E-cadherin-catenin complex possesses the ability to downmodulate NF-κB activity, which leads to inflammation-associated carcinogenesis [57]. There is also the epigenetic mechanism controlling the E-cadherin action directly associated with expression of microRNAs, microRNA-9 and microRNA-10b [58]. A recent study described tumor derived exosomes that tend to transfer EMT-related RNAs and proteins to recipient cells, mediate the instability of cadherins, and promote cancer progression [59]. The other tumor suppressing mechanism by E-cadherin complexes may be associated with the RNA interference (RNAi) machinery at epithelial AJs [60]. However, these novel findings require further examination.
Cadherin switching is primarily the result of transcriptional regulation of cadherin expression through several factors, such as SNAI1, SLUG, TWIST, ZEB1 and ZEB2 [61,62]. These factors act through repression of E-cadherin transcription by directly binding to its promoter [63]. The main transcriptional activation of EMT are the Wnt/β catenin, TGF-β and Hedgehog signaling pathways [62,63,64,65]. In addition, signaling molecules such as ILK, FAK and SRC have an impact on the activation of EMT [66]. TGF- β, in co-operation with Ras, induces Snail and Slug, which then leads to the disruption of desmosomes followed by cell motility, inhibition of cytokeratin expression and increase in vimentin expression. Finally, cell spreading occurs leading to separation of cell-cell attachment [67,68,69]. The Wnt/catenin and TGF- β signaling pathways in EMT process are quite similar and have been shown in breast cancer bone metastasis [70].
The protein p120 catenin is another important factor that plays a role in the regulation of downstream signaling and cell behavior upon cadherin switch [55,71]. p120 is encoded by CTNND1 gene, and functions to maintain the stability and turnover of E-cadherin as well as regulate Rho GTPases [72]. The loss or inactivity of E-cadherin leads to translocation of p120 to the cytosol, where p120 now can control the invasiveness of tumor cells [72,73]. It activates the Rac1-MAPK (mitogen-activated protein kinase) signaling pathway and promotes transformed cell growth [55]. Moreover, when E-cadherin expression switches to P-cadherin, further cytosolic translocation of p120 occurs leading to induction of tumor cell migration through activation of RAC1 and CDC42 [74,75], tumor anchorage-independence and increased tumor growth in vivo [76]. The tumor invasiveness and cell migration are increased by the upregulation of mesenchymal cadherins and the downregulation of E-cadherins in tumors of epithelial origin. However, pro-tumorigenic cell behavior may be triggered by the expression of mesenchymal cadherins even in the presence of E-cadherin [77].
In humans, the loss of E-cadherin expression during EMT is associated with tumor development. However, decreased expression of E-cadherin has also been observed in canines with more aggressive mast cell tumors (Grade 3) [78]. Similarly, the change in expression of E-cadherin to N-cadherin or the up-regulation of cadherin-11 and P-cadherin also favor tumor progression and are an indicator of more migratory and more invasive tumor types [11]. In many studies, it was shown that high expression of E-cadherin was associated with prevention of tumor progression into a more invasive type [55,79]. Therefore, E-cadherin up-regulation can be associated with inhibition of tumor cell invasion, and can also be considered a tumor suppressor [17,19].

5. Cadherins in Human and Animal Cancer as a Prognostic Factor

Cadherin expression has been widely studied in human cancers as well as in animal models [4,10,21]. Expression of different cadherins in cancer is diverse and multifactorial.
P-cadherin is expressed in myoepithelial cells, and its overexpression in high-grade tumors is correlated with tumor aggressiveness and a poor prognosis in humans [4]. Similarly, in canine, malignant mammary tumors anomalous expression of P-cadherin was associated with invasion [81]. It was demonstrated that in cats, P-cadherin expression is significantly related to high histological grade of carcinomas, tumor necrosis, infiltrative growth and presence of neoplastic emboli [82]. However, in human squamous cell carcinoma of the oral cavity (OSCC), the reduced expression of P-cadherin and E-cadherin contributed to the invasive potential of early OSCC and was associated with poor prognosis [83]. According to Kim et al., in gastric carcinomas the expression of P-cadherin was intact, while no expression of P-cadherin was detected in non-neoplastic gastric mucosal tissues from gastric carcinoma patients. Additionally, the P-cadherin gene from gastric carcinoma was hypomethylated in its promoter region, whereas the same gene in non-carcinoma cells was methylated. Such presentation of P-cadherin expression was associated with favorable prognosis [84]. On the other hand, in vitro experiments on a pancreatic ductal adenocarcinoma (PDAC) cell line that does not express P-cadherin showed that ectopic expression of P-cadherin (Panc1-CDH3) allowed the PDAC cells to acquire increased motility, which, however, could be blocked by an antibody against P-cadherin. These data provide the evidence that overexpression of P-cadherin is likely related to the biological aggressiveness of PDACs [85]. A closer examination of the prognostic value of the cadherin switch during bladder cancer shows that while the decrease of E-cadherin and the gain of N-cadherin gene expression represented risk factors for cancer-related death, the expression of P-cadherin proved to be a significant independent prognostic factor for both cancer-specific and recurrence-free survival [86]. In pursuit of potential diagnostic usefulness of P-cadherin, Riener et al. [87] used immunohistochemistry on tissue microarrays to evaluate carcinomas and dysplastic lesions of the biliary tract. They detected P-cadherin in most of extrahepatic cholangiocarcinomas (73%) and gallbladder carcinomas (64%) and in some of intrahepatic cholangiocarcinomas (37%). Dysplastic biliary epithelium highly expressed P-cadherin. In those studies, P-cadherin was detected at early stage of carcinogenesis and was, therefore, thought to be a useful marker for the early detection of cholangiocarcinoma. In yet another study involving 69 patients with hepatocellular carcinoma, over half of the liver samples exhibited downregulation of P-cadherin compared to primary human hepatocytes and non-malignant liver tissue. In these cases, reduced expression of P-cadherin induced tumorigenicity and was deemed as a prognostic marker of this highly aggressive hepatocellular carcinoma [88]. In summary, expression P-cadherin appears to be dependent on the type of cancer, and therefore, its prognostic value cannot be generalized.
N-cadherin (the product of the CDH2 gene) influences the nervous system, brain, heart, skeletal muscles, blood vessels and hematopoietic microenvironment function [89,90,91]. N-cadherin is overexpressed in invasive and metastatic breast cancer and induces metastasis by potentiating signaling by the FGF receptor in humans [10]. There are various factors which modulate N-cadherin expression in tumor cells such as TGF-β1, Wnt/β-catenin, EGFR and NF-κB. Abnormal expression of N-cadherin has also been found in many other cancers, such as lung cancer, hepatic cancer, urothelial cancer and prostate cancer. [89,90,91,92,93,94]. In tumor progression, it has been documented that abnormal expression of N-cadherin is connected with malignancies manifested by cell transformation, apoptosis, angiogenesis, invasion and metastasis [89]. Conversely, in canine choroid plexus tumors, N-cadherin immunolabeling was more expressed in grade I tumors [95]. In feline adenomas and carcinomas, N-cadherin expression is associated with a reduced expression of E-cadherin and the presence of regional metastasis [96]. High presence of N-cadherin in colorectal cancer significantly associated with tumor differentiation, tumor size, tumor nodes and metastasis stage. Lower overall survival and disease-free survival rate was characteristic for patients with high N-cadherin expression compared to patients who had low N-cadherin expression. According to this study, high N-cadherin expression in colorectal cancer was an independent prognostic factor [97]. Lascombe et al. [98] reported that normal urothelium did not express N-cadherin but observed increased expression in advanced stage superficial urothelial tumors and proposed N-cadherin as a novel prognostic marker of progression in superficial urothelial tumors. It appears that expression of N-cadherin may have varied significance depending on the tumor type. For instance, a physiological pattern of N-cadherin expression was observed in renal cell carcinoma (RCC) specimens from patients undergoing surgery, despite a high tumor grade, and patients with RCC and normal N-cadherin-expression had a poorer prognosis than those with N-cadherin-abnormal RCC [99]. Therefore, this type of cadherin may play a different role from that of E-cadherin and may be associated with the aggressiveness and malignant potential of RCC.
The most frequently evaluated cadherin is E-cadherin [20]. This adhesion molecule is an important component of the apical zonula adherents in the epithelial monolayers and is a regulator of the epithelial structure [17,100,101]. A recent meta-analysis of breast cancer patients carried out by Li et al. [102] revealed that reduction of E-cadherin on tumor cells was significantly associated with poorer overall survival and disease-free survival, and correlated with clinicopathological features such as tumor size, lymph node status, TNM stage and histological grade [18,103]. E-cadherin expression has also been studied in animal models. However, in veterinary species, the involvement of E-cadherin in cancers is just beginning to be unraveled. For instance, in mammary gland tumors of bitches, decreased expression of E-cadherin is associated with tumor malignancy and metastatic progression, which leads to shorter patient survival [103,104]. Zuccari et al. showed low expression of E-cadherin in canine mammary neoplasia and considered it as a marker of favorable prognosis. However, when cachexia and obesity in affected dogs occurred with low E-cadherin expression, an unfavorable prognosis was obvious [105]. The conflicting results suggest that more studies on this field should be done. On the other hand, a study of 93 dogs with canine cutaneous histiocytoma (CCH) revealed that the lack of E-cadherin expression on tumor cells might indicate an activation or maturation process of the tumor cells accounting for a switch to CCH regression [106]. A similar expression pattern of E-cadherin has been detected during carcinogenesis of the canine prostatic epithelial cells, [107], canine and feline meningiomas [108] and ovine intestinal adenocarcinoma [109]. Because of some similarities in the behavior of cadherin, animal tumors should be explored as comparative models for studies in human cancers to better understand the role of E-cadherin in tumorigenesis. Therefore, low-expression of E-cadherin can stand in as a predictor of poorer prognosis and could be a valuable therapeutic target for breast cancer patients.
In dogs, reduction in E-cadherin expression, like humans, is associated with increased tumor size, high histological and invasion grades, lymph node metastasis and a high mitotic index [21]. Another study has demonstrated that the expression of classical cadherins is altered during tumor progression in feline neoplasms [96]. In addition, E-cadherin in feline mammary tumors demonstrated its reduction or absent expression in carcinomas when compared to benign lesions [110]. On the other hand, the prognostic value of E-cadherin in feline carcinomas is still unknown. Regarding the prognostic value of E-cadherin in different types of cancer, in a large series of RCC with tumor thrombus (TT) of vena cava (VC), increased expression of E-cadherin was connected with initial lymph node metastasis and with both worse OS (overall survival) and worse CSS (cause-specific survival). Such presentation of E-cadherin may aid in identifying recurrence risk patients in whom adjuvant therapy could be beneficial. E-cadherin overexpression in sarcomas reduces anchorage-independent growth and spheroid formation of sarcoma cells through downregulation of phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, thus inhibiting sarcoma aggressiveness by preventing anchorage-independent growth [111]. In metastatic colorectal cancer (mCRC), expression of E-cadherin in either cell membrane or cytoplasm was combined with strong vascular endothelial growth factor A (VEGF-A) staining as a predictor of disease outcome. VEGF-A expression was significantly connected with E-cadherin expression in the cytoplasm. Both enhanced E-cadherin expression in the cytoplasm and decreased expression of E-cadherin in the cell membrane indicate a poor prognosis in mCRC [112]. Besides the protein expression levels of E-cadherin, the genetic variation of CDH1 gene in dogs appears to be important. Of the three known single nucleotide polymorphisms (SNP) of CDH1, rs850805755, rs852280880 and rs852639930, rs850805755 and rs852280880 were associated with a decreased risk and a later onset of mammary tumor development. Furthermore, these SNPs were characterized by small size carcinomas, low histological grade and low nuclear pleomorphism. On the hand, SNP rs852639930 was characterized by a non-infiltrative, non-invasive growth pattern and development of small size tumors. Therefore, these SNP variants may indicate a low tumor development [113].

6. Therapeutic Targets Associated with Cadherin Dysfunction

Understanding how cadherins influence the cell behavior can be used to design possible therapeutic interventions to regulate its activity and prevent tumor cell growth, invasion and metastasis [12,114].
A good example is α-solanine (a glycoalkaloid extract of Solanum nigrum Linn.), which stimulates E-cadherin expression and reduce vimetin expression (mesenchymal marker) leading to the suppression of EMT. At the same time α-solanine downregulates matrix metalloproteinase (MMP) expression, which plays a key role in metastatic process; therefore, it is has a strong anti-carcinogenic activity [115]. Additionally, drugs such as simvastatin and metformin upregulate E-cadherin and inhibit N-cadherin in human prostate cancer cells, contributing to blockade of TGF-β1-induced EMT [116,117].
Many synthetic peptides are used in cancer therapy. In recent studies ADH-1 synthetic cyclic peptide, which mimics the natural HAVD sequence of N-cadherin, has been used in myeloma, neuroblastoma and pancreatic cancer in vitro [118,119,120]. It leads to inhibition of angiogenesis, metastasis, cell proliferation and tumor growth. A murine pancreatic cancer model tested the therapeutic potential of ADH-1, an antagonist of N-cadherin. Results showed that ADH-1 has significant antitumor activity against N-cadherin–expressing pancreatic cancer cells [120]. Human clinical trials also confirmed the antitumor activity of ADH-1 in gynecological cancers [121]. Other N-cadherin antagonists, synthetic linear peptide H-SWTLYTPSGQSK-NH 2 blocked neurite outgrowth, myoblast fusion and cell migration in breast cancer in vivo [122]. In addition, monoclonal antibodies can be used in cancer therapy. Antibodies against N-cadherin inhibit the metastases and suppress tumor growth in prostate cancer in vivo [123].
Other therapeutic targets may be epigenetic activation of E-cadherin or inactivation of N-cadherin. In different types of cancer increased invasiveness is connected with downregulation of the E-cadherin-encoding gene (CDH1). In human breast, hepatocellular and prostate cancer hypermethylation of the CDH1 promoter has been observed [124,125]. It was documented that decreased DNA methylation leads to inhibition of tumor growth in a mouse model for colorectal tumor; thus, this can be a novel target for anticancer therapy [126]. For instance, thymine-DNA-glycosylase (TDG) has been directly targeted to specific sequences in the DNA to produce local DNA demethylation at critical regulatory sequences and lead to enhanced gene induction [125]. Another idea is to target an intramembrane protease of the Rhomboid family-RHBDL2 to control cancer cell migration by E-cadherin functional inactivation [127]. As mentioned earlier, activation of Wnt/β-catenin signaling is important for the initiation and progression of cancers of different tissues. It seems, therefore, that targeting inhibition of Wnt/β-catenin signaling could be a rational approach for the therapy of cancers of various origins [128]. To this extent, targeting cadherin-17 gene (CDH17) through RNA interference–mediated knockdown inhibited proliferation of both primary and highly metastatic HCC cell lines in vitro and in vivo [129]. Moreover, it was demonstrated that the N-cadherin knockdown (CDH2) led to the inhibition of invasion of human melanoma cells [130]. In addition, the downregulation of N-cadherin lowers the invasiveness of esophageal squamous cell carcinomas in vitro [131].

7. Conclusions

Cadherins play an important role in tissue homeostasis and dysfunction. Destabilization of cadherin-catenin complex may result in tumor progression. Cadherins show varied biological functions. The loss of E-cadherin expression during EMT in humans is associated with tumor development and worse prognosis. For these reasons, many studies have shown that E-cadherin can act as tumor suppressor; however, more recently, a role in the cancer progression has been also described.
Many oncogenic signaling pathways modify cadherin cell-cell adhesion. The most commonly described are cyclin kinase inhibitor p27-mediated signaling, MAPK, Ras, Rac1 signaling, PI3K/AKT signaling, as well as Hippo signaling. Abnormal cadherins expression is connected to metastasis, angiogenesis, adhesion and invasion.
Higher expression of N-cadherins is related to tumor aggressiveness, cancer metastasis, apoptosis and angiogenesis in many human and animal cancers.
Overexpression of P-cadherin is also usually a bad prognostic factor, as it is related to tumor progression and invasion and shorter overall survival.
Overall, these adhesion molecules are novel promising targets in cancer treatment, but they may also be useful in predicting a patient’s prognosis in human and veterinary medicine.

Author Contributions

Conceptualization, I.K.; writing—original draft preparation, I.K., O.W.-P. and Z.N.; writing—review and editing, I.K., O.W.-P., Z.N., B.D.-K., F.N.T. and P.J.; supervision, P.J.; project administration, I.K.; funding acquisition, I.K. and P.J.; All authors have read and agreed to the published version of the manuscript.

Funding

Publication was funded by KNOW (Leading National Research Centre) Scientific Consortium “Healthy Animal- Safe Food,” Ministry of Science and Higher Education No. 05-1/KNOW2/2015.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

APCAdenomatous polyposis coli
ARVCFArmadillo repeat protein deleted in velo-cardio-facial syndrome
CCHCanine cutaneous histiocytoma
CSSCause specific survival
EMTEpithelial mesenchymal transition
E-cadherinEpithelial cadherin
ECExtracellular domain
GSK-3βKinase glycogen synthase 3β
LEFLymphoid enhancer factor
MAPKMitogen activated kinase
MCRCMetastatic colorectal cancer
MMPMatrix metaloproteinase
N-cadherinNeural cadherin
NPRAP/δ-cateninNeural plakophilin-related armadillo protein, CTNND2
OSOverall survival
OSCCSquamous cell carcinoma of the oral cavity
p0071Plakophilin 4
p120Phosphorylated CREB1
p-CREBp120 catenin, also known as CTNND1
PDACpancreatic ductal adenocarcinoma
PI3KPhosphoinositide 3-kinase
P-cadherinPlacental cadherin
RasRat sarcoma viral oncogene
Rac1Rhomboid-like-2
RCCRas-related C3 botulinum toxin substrate
RHBDL2Renal cell carcinoma
RTKReceptor tyrosine kinase
SNPSingle nucleotide pleomorphism
SnailTranscription factor Snail, also known as SNAI1
SlugTranscription factor Slug, also known as SNAI2
TCFT-cell factor
TDGThymine-DNA-glycosylase
TGF-βTransforming growth factor β
TTTumor thrombus
VEGF-AVascular endothelial growth factor A
VCVena cava

References

  1. Colás-Algora, N.; Millán, J. How many cadherins do human endothelial cells express? Cell Mol. Life Sci. 2019, 76, 1299–1317. [Google Scholar] [CrossRef] [PubMed]
  2. Oda, H.; Takeichi, M. Evolution: Structural and functional diversity of cadherin at the adherens junction. J. Cell Biol. 2011, 193, 1137–1146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Shapiro, L.; Weis, W.I. Structure and biochemistry of cadherins and catenins. Cold Spring Harb. Perspect. Biol. 2009, 1, a003053. [Google Scholar] [CrossRef] [PubMed]
  4. Casal, J.I.; Bartolome, R.A. Beyond N-cadherin, relevance of cadherins 5,6 and 17 in cancer progression and metastasis. Int. J. Mol. Sci. 2019, 20, 3373. [Google Scholar] [CrossRef] [Green Version]
  5. Weis, W.I. Cadherin structure: A revealing zipper. Structure 1995, 3, 425–427. [Google Scholar] [CrossRef] [Green Version]
  6. Bruner, H.C.; Derksen, P.W.B. Loss of E-Cadherin-Dependent Cell-Cell Adhesion and the Development and Progression of Cancer. Cold Spring Harb. Perspect. Biol. 2018, 10, a029330. [Google Scholar] [CrossRef] [Green Version]
  7. Troyanovsky, R.B.; Chitaev, N.A.; Troyanovsky, S.M. Cadherin binding sites of plakoglobin: Localization, specificity and role in targeting to adhering junctions. J. Cell Sci. 1996, 109, 3069–3078. [Google Scholar]
  8. Grigorian, I.Y.; Linkova, N.S.; Polyakova, V.O.; Paltseva, E.M.; Kozlov, K.L. Signaling molecules of the endometrium: Gerontological and general pathological aspects. Adv. Gerontol. 2016, 6, 36–43. [Google Scholar] [CrossRef]
  9. Sousa, B.; Pereira, J.; Paredes, J. The Crosstalk Between Cell Adhesion and Cancer Metabolism. Int. J. Mol. Sci. 2019, 20, 1933. [Google Scholar] [CrossRef] [Green Version]
  10. Baranwal, S.; Alahari, S.K. Molecular mechanisms controlling E-cadherin expression in breast cancer. Biochem. Biophys. Res. Commun. 2009, 384, 6–11. [Google Scholar] [CrossRef] [Green Version]
  11. Roggiani, F.; Mezzanzanica, D.; Rea, K.; Tomassetti, A. Guidance of Signaling Activations by Cadherins and Integrins in Epithelial Ovarian Cancer Cells. Int. J. Mol. Sci. 2016, 17, 1387. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Dalle Vedove, A.; Falchi, F.; Donini, S.; Dobric, A.; Germain, S.; Di Martino, G.P.; Prosdocimi, T.; Vettraino, C.; Torretta, A.; Cavalli, A.; et al. Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell-Cell Adhesion. Int. J. Mol. Sci. 2019, 20, 3404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Winter, J.M.; Ting, A.H.; Vilardell, F.; Gallmeier, E.; Baylin, S.B.; Hruban, R.H.; Kern, S.E.; Iacobuzio-Donahue, C.A. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin. Cancer Res. 2008, 14, 412–418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Andrews, J.L.; Kim, A.C.; Henscor, J.R. The role and function of cadherins in the mammary gland. Breast Cancer Res. 2012, 14, 203. [Google Scholar] [CrossRef] [Green Version]
  15. Gruss, C.; Herlyn, M. Role of cadherins and matrixins in melanoma. Curr. Opin. Oncol. 2001, 13, 117–123. [Google Scholar] [CrossRef]
  16. Rossi, T.; Tedaldi, G.; Petracci, E.; Khouzam, R.A.; Ranzani, G.N.; Morgagni, P.; Saragoni, L.; Monti, M.; Calistro, D.; Ulivi, P.; et al. E-cadherin downregulation and microRNAs in sporadic intestinal-type gastric cancer. Int. J. Mol. Sci. 2019, 20, 4452. [Google Scholar] [CrossRef] [Green Version]
  17. Kourtidis, A.; Lu, R.; Pence, L.J.; Anastasiadis, P.Z. A central role for cadherin signaling in cancer. Exp. Cell Res. 2017, 358, 78–85. [Google Scholar] [CrossRef]
  18. Ceresa, D.; Alessandrini, F.; Bosio, L.; Marubbi, D.; Reverberi, D.; Malatesta, P.; Appolloni, I. Cdh4 Down-Regulation Impairs in Vivo Infiltration and Malignancy in Patients Derived Glioblastoma Cells. Int. J. Mol. Sci. 2019, 20, 4028. [Google Scholar] [CrossRef] [Green Version]
  19. Shimada, S.; Mimata, A.; Sekine, M.; Mogushi, K.; Akiyama, Y.; Fukamachi, H.; Jonkers, J.; Tanaka, H.; Eishi, Y.; Yuasa, Y. Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer. Gut 2012, 61, 344–353. [Google Scholar] [CrossRef]
  20. Daulagala, A.C.; Bridges, M.C.; Kourtidis, A. E-cadherin Beyond Structure: A signaling hub in colon homeostasis and disease. Int. J. Mol. Sci. 2019, 20, 2756. [Google Scholar] [CrossRef] [Green Version]
  21. Shamir, E.R.; Ewald, A.J. Adhesion in mammary development: Novel roles forE-cadherin in individul and collective cell migration. Curr. Top. Dev. Biol. 2015, 112, 353–382. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Labernadie, A.; Kato, T.; Brugues, A.; Serra-Picamal, X.; Derzsi, S.; Arwert, E.; Weston, A.; Gonzalez-Tarrago, V.; Elosegui-Artola, A.; Albertazzi, L.; et al. A mechanically active heterotypic E-cadherin- N-cadherin adhesion enables fibroblast to drive cancer cell invasion. Nat. Cell. Biol. 2017, 19, 224–237. [Google Scholar] [CrossRef] [PubMed]
  23. Dohn, M.R.; Brown, M.V.; Reynolds, A.B. An essential role for p120-catenin in Src- and Rac1-mediated anchorage-independent cell growth. J. Cell Biol. 2009, 184, 437–450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Venhuizen, J.H.; Span, P.N.; van den Dries, K.; Sommer, S.; Friedl, P.; Zegers, M.M. P120 catenin isoforms differentially associate with breast cancer invasion and metastasis. Cancers 2019, 11, 1459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Petrova, Y.I.; Schecterson, L.; Gumbiner, B.M. Roles for E- cadherin cell surface regulation in cancer. Mol. Biol. Cell. 2016, 27, 3233–3244. [Google Scholar] [CrossRef] [PubMed]
  26. Gurrapu, S.; Franzolin, G.; Fard, D.; Accardo, M.; Medico, E.; Sarotto, I.; Sapino, A.; Isella, C.; Tamagnone, L. Reverse signaling by semaphorin 4 C elicits SMAD1/5- and ID1/3- dependent invasive reprogramming in cancer cells. Sci. Signal. 2019, 12, eaav2041. [Google Scholar] [CrossRef] [PubMed]
  27. Padmanaban, V.; Krol, I.; Suhali, Y.; Szczerba, B.M.; Aceto, N.; Bader, J.S.; Ewald, A.J. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 2019, 573, 439–444. [Google Scholar] [CrossRef]
  28. Yamada, S.; Pokutta, S.; Drees, F.; Weis, W.I.; Nelson, W.J. Deconstructing the cadherin-catenin-actin complex. Cell 2005, 123, 889–901. [Google Scholar] [CrossRef] [Green Version]
  29. Gama, A.; Schmitt, F. Cadherin cell adhesion system in canine mammary cancer: A review. Vet. Med. Int. 2012, 2012, 357187. [Google Scholar] [CrossRef] [Green Version]
  30. Tanaka, T.; Iino, M.; Goto, K. Knockdown of Sec6 improves cell–cell adhesion by increasing α-E-catenin in oral cancer cells. FEBS Lett. 2012, 586, 924–933. [Google Scholar] [CrossRef] [Green Version]
  31. Polakis, P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol. 2012, 4, a008052. [Google Scholar] [CrossRef] [Green Version]
  32. Chamorro, M.N.; Schwartz, D.R.; Vonica, A.; Brivanlou, A.H.; Cho, K.R.; Varmus, H.E. FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J. 2005, 24, 73–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Clevers, H. Wnt/β-Catenin Signaling in Development and Disease. Cell 2006, 127, 469–480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Heuberger, J.; Birchmeier, W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb. Perspect. Biol. 2010, 2, a002915. [Google Scholar] [CrossRef]
  35. Kazanskaya, O.; Glinka, A.; del Barco Barrantes, I.; Stannek, P.; Niehrs, C.; Wu, W. R-Spondin2 Is a Secreted Activator of Wnt/β-Catenin Signaling and Is Required for Xenopus Myogenesis. Dev. Cell 2004, 7, 525–534. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Khan, Z.; Vijayakumar, S.; de la Torre, T.V.; Rotolo, S.; Bafico, A. Analysis of endogenous LRP6 function reveals a novel feedback mechanism by which Wnt negatively regulates its receptor. Mol. Cell Biol. 2007, 27, 7291–7301. [Google Scholar] [CrossRef] [Green Version]
  37. MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev. Cell 2009, 17, 9–26. [Google Scholar] [CrossRef] [Green Version]
  38. Kourtidis, A.; Yanagisawa, M.; Huveldt, D.; Copland, J.A.; Anastasiadis, P.Z. Pro-tumorigenic phosphorylation of p 120 catenin in renal and breast cancer. PLoS ONE 2015, 10, e0129964. [Google Scholar] [CrossRef] [Green Version]
  39. Andl, C.D.; Fargnoli, B.B.; Okawa, T.; Bowser, M.; Takaoka, M.; Nakagawa, H.; Klein-Szanto, A.; Herlyn, M.; Rustgi, A.K. Coordinated functions of E-cadherin and transforming Growth Factor β receptor II in vitro and in vivo. Cancer Res. 2006, 66, 9878–9885. [Google Scholar] [CrossRef] [Green Version]
  40. Pece, S.; Gutkind, J.S. Signaling from E-cadherins to the MAPK pathway by the recuitment and activation of epidermal growth factor receptors upon cell-cell contact formation. J. Biol. Chem. 2000, 275, 41227–41233. [Google Scholar] [CrossRef] [Green Version]
  41. Motti, M.L.; Califano, D.; Baldassarre, G.; Celetti, A.; Merolla, F.; Forzati, F.; Napolitano, M.; Tavernise, B.; Fusco, A.; Viglietto, G. Reduced E-cadherin expression contributes to the loss of p27 kip1 -mediated mechanism of contact inhibition in thyroid anaplastic carcinomas. Carcinogenesis 2005, 26, 1021–1034. [Google Scholar] [CrossRef]
  42. St Croix, B.; Sheehan, C.; Rak, J.W.; Flørenes, V.A.; Slingerland, J.M.; Kerbel, R.S. E-Cadherin-dependent growth suppression is mediated by the cyclin-dependent kinase inhibitor p27(KIP1). J. Cell Biol. 1998, 142, 557–571. [Google Scholar] [CrossRef] [PubMed]
  43. De Santis, G.; Miotti, S.; Mazzi, M.; Canevari, S.; Tomassetti, A. E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells. Oncogene 2009, 28, 1206–1217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Pang, J.H.; Kraemer, A.; Stehbens, S.J.; Frame, M.C.; Yap, A.S. Recruitment of Phosphoinositide 3-Kinase Defines a Positive Contribution of Tyrosine Kinase Signaling to E-cadherin Function. J. Biol. Chem. 2005, 280, 3043–3050. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Pece, S.; Chiariello, M.; Murga, C.; Gutkind, J.S. Activation of the Protein Kinase Akt/PKB by the Formation of E-cadherin-mediated Cell-Cell Junctions: Evidence for the association of phosphatidylinositol 3-kinase with the e-cadherin adhesion complex. J. Biol. Chem. 1999, 274, 19347–19351. [Google Scholar] [CrossRef] [Green Version]
  46. Kim, N.G.; Koh, E.; Chen, X.; Gumbiner, B.M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl. Acad. Sci. USA 2011, 108, 11930–11935. [Google Scholar] [CrossRef] [Green Version]
  47. McCrea, P.D.; Maher, M.T.; Gottardi, C.J. Nuclear signaling from cadherin adhesion complexes. Curr. Top. Dev. Biol. 2015, 112, 129–196. [Google Scholar] [CrossRef] [Green Version]
  48. Forbes, S.A.; Bindal, N.; Bamford, S.; Cole, C.; Kok, C.Y.; Beare, D.; Jia, M.; Shepherd, R.; Leung, K.; Menzies, A.; et al. COSMIC: Mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011, 39, D945–D950. [Google Scholar] [CrossRef] [Green Version]
  49. Yang, K.; Wang, X.; Zhang, H.; Wang, Z.; Nan, G.; Li, Y.; Zhang, F.; Mohammed, M.K.; Haydon, R.C.; Luu, H.H.; et al. The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: Implications in targeted cancer therapies. Lab. Investig. 2016, 96, 116–136. [Google Scholar] [CrossRef] [Green Version]
  50. Gloushankova, N.A.; Zhitnyak, I.Y.; Rubtsova, S.N. Role of Epithelial-Mesenchymal Transition in Tumor Progression. Biochemistry 2018, 83, 1469–1476. [Google Scholar] [CrossRef]
  51. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Nieto, M.A.; Huang, R.Y.-J.; Jackson, R.A.; Thiery, J.P. EMT: 2016. Cell 2016, 166, 21–45. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Hazan, R.B.; Qiao, R.; Keren, R.; Badano, I.; Suyama, K. Cadherin Switch in Tumor Progression. Ann. N. Y. Acad. Sci. 2004, 1014, 155–163. [Google Scholar] [CrossRef] [PubMed]
  54. Wong, A.S.T.; Gumbiner, B.M. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J. Cell Biol. 2003, 161, 1191–1203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Soto, E.; Yanagisawa, M.; Marlow, L.A.; Copland, J.A.; Perez, E.A.; Anastasiadis, P.Z. p120 catenin induces opposing effects on tumor cell growth depending on E-cadherin expression. J. Cell Biol. 2008, 183, 737–749. [Google Scholar] [CrossRef] [Green Version]
  56. Pećina-Slaus, N. Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int. 2003, 3, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Cowell, C.F.; Yan, J.K.; Eiseler, T.; Leightner, A.C.; Döppler, H.; Storz, P. Loss of cell-cell contacts induces NF-κB via RhoA-mediated activation of protein kinase D1. J. Cell Biochem. 2009, 106, 714–728. [Google Scholar] [CrossRef] [Green Version]
  58. Wong, T.S.; Gao, W.; Chan, J.Y. Interactions between E-cadherin and microRNA deregulation in head and neck cancers: The potential interplay. Biomed. Res. Int. 2014, 2014, 126038. [Google Scholar] [CrossRef] [Green Version]
  59. Wang, B.; Tan, Z.; Guan, F. Tumor-derived exosomes mediate the instability of cadherins and promote tumor progression. Int. J. Mol. Sci. 2019, 20, 3652. [Google Scholar] [CrossRef] [Green Version]
  60. Kourtidis, A.; Anastasiadis, P.Z. Close encounters of the RNAi kind: The silencing life of the adherens junctions. Curr. Opin. Cell Biol. 2018, 54, 30–36. [Google Scholar] [CrossRef]
  61. Tam, W.L.; Weinberg, R.A. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 2013, 19, 1438–1449. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Wheelock, M.J.; Shintani, Y.; Maeda, M.; Fukumoto, Y.; Johnson, K.R. Cadherin switching. J. Cell Sci. 2008, 121, 727–735. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Yang, J.; Weinberg, R.A. Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis. Dev. Cell 2008, 14, 818–829. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Katoh, Y.; Katoh, M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA (review). Int. J. Mol. Med. 2008, 22, 271–275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Scheel, C.; Eaton, E.N.; Li, S.H.-J.; Chaffer, C.L.; Reinhardt, F.; Kah, K.-J.; Bell, G.; Guo, W.; Rubin, J.; Richardson, A.L.; et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011, 145, 926–940. [Google Scholar] [CrossRef] [Green Version]
  66. Cichon, M.A.; Radisky, D.C. Extracellular matrix as a contextual determinant of transforming growth factor-β signaling in epithelial-mesenchymal transition and in cancer. Cell Adhes. Migr. 2014, 8, 588–594. [Google Scholar] [CrossRef] [Green Version]
  67. Boyer, B.; Tucker, G.C.; Vallés, A.M.; Franke, W.W.; Thiery, J.P. Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells. J. Cell Biol. 1989, 109, 1495–1509. [Google Scholar] [CrossRef] [PubMed]
  68. Horiguchi, K.; Shirakihara, T.; Nakano, A.; Imamura, T.; Miyazono, K.; Saitoh, M. Role of Ras Signaling in the Induction of Snail by Transforming Growth Factor-β. J. Biol. Chem. 2009, 284, 245–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Lu, Z.; Ghosh, S.; Wang, Z.; Hunter, T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of β-catenin, and enhanced tumor cell invasion. Cancer Cell 2003, 4, 499–515. [Google Scholar] [CrossRef] [Green Version]
  70. Kang, Y.; He, W.; Tulley, S.; Gupta, G.P.; Serganova, I.; Chen, C.-R.; Manova-Todorova, K.; Blasberg, R.; Gerald, W.L.; Massagué, J. Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc. Natl. Acad. Sci. USA 2005, 102, 13909–13914. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Kourtidis, A.; Ngok, S.P.; Anastasiadis, P.Z. p120 catenin: An essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog. Mol. Biol. Transl. Sci. 2013, 116, 409–432. [Google Scholar] [CrossRef] [Green Version]
  72. Bellovin, D.I.; Bates, R.C.; Muzikansky, A.; Rimm, D.L.; Mercurio, A.M. Altered Localization of p120 Catenin During Epithelial to Mesenchymal Transition of Colon Carcinoma Is Prognostic for Aggressive Disease. Cancer Res. 2005, 65, 10938–10945. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Paredes, J.; Correia, A.L.; Ribeiro, A.S.; Milanezi, F.; Cameselle-Teijeiro, J.; Schmitt, F.C. Breast carcinomas that co-express E- and P-cadherin are associated with p120-catenin cytoplasmic localisation and poor patient survival. J. Clin. Pathol. 2008, 61, 856–862. [Google Scholar] [CrossRef] [PubMed]
  74. Smith, A.L.; Dohn, M.R.; Brown, M.V.; Reynolds, A.B. Association of Rho-associated protein kinase 1 with E-cadherin complexes is mediated by p120-catenin. Mol. Biol. Cell 2012, 23, 99–110. [Google Scholar] [CrossRef]
  75. Cheung, L.W.T.; Leung, P.C.K.; Wong, A.S.T. Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer. Oncogene 2010, 29, 2427–2440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Schackmann, R.C.J.; van Amersfoort, M.; Haarhuis, J.H.I.; Vlug, E.J.; Halim, V.A.; Roodhart, J.M.L.; Vermaat, J.S.; Voest, E.E.; van der Groep, P.; van Diest, P.J.; et al. Cytosolic p120-catenin regulates growth of metastatic lobular carcinoma through Rock1-mediated anoikis resistance. J. Clin. Investig. 2011, 121, 3176–3188. [Google Scholar] [CrossRef] [PubMed]
  77. Nieman, M.T.; Prudoff, R.S.; Johnson, K.R.; Wheelock, M.J. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J. Cell Biol. 1999, 147, 631–644. [Google Scholar] [CrossRef] [Green Version]
  78. Mackowiak, I.I.; Gentile, L.B.; Chaible, L.M.; Nagamine, M.K.; Guerra, J.M.; Mota, E.F.F.; Matera, J.M.; Mennecier, G.; Sanches, D.S.; Dagli, M.L.Z. E-cadherin in canine mast cell tumors: Decreased expression and altered subcellular localization in Grade 3 tumors. Vet. J. 2012, 194, 405–411. [Google Scholar] [CrossRef] [Green Version]
  79. Gottardi, C.J.; Wong, E.; Gumbiner, B.M. E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J. Cell Biol. 2001, 153, 1049–1060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  80. Albrecht, L.V.; Green, K.J.; Dubash, A.D. Cadherins in Cancer. In The Cadherin Superfamily; Suzuki, S., Hirano, S., Eds.; Springer: Tokyo, Japan, 2016. [Google Scholar] [CrossRef]
  81. Figueira, A.C.; Teodósio, A.S.; Carvalheira, J.; Lacerda, M.; de Matos, A.; Gärtner, F. P-cadherin expression in feline mammary tissues. Vet. Med. Int. 2012, 2012, 687424. [Google Scholar] [CrossRef] [Green Version]
  82. Ribeiro, A.S.; Albergaria, A.; Sousa, B.; Correia, A.L.; Bracke, M.; Seruca, R.; Schmitt, F.C.; Paredes, J. Extracellular cleavage and shedding of P-cadherin: A mechanism underlying the invasive behaviour of breast cancer cells. Oncogene 2010, 29, 392–402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Muñoz-Guerra, M.F.; Marazuela, E.G.; Fernández-Contreras, M.E.; Gamallo, C. P-cadherin expression reduced in squamous cell carcinoma of the oral cavity. Cancer 2005, 103, 960–969. [Google Scholar] [CrossRef] [PubMed]
  84. Kim, M.A.; Jung, E.J.; Lee, H.S.; Lee, H.E.; Yang, H.-K.; Oh, D.-Y.; Bang, Y.-J.; Kim, W.H. P-cadherin expression in gastric carcinoma: Its regulation mechanism and prognostic significance. Hum. Pathol. 2010, 41, 877–885. [Google Scholar] [CrossRef] [PubMed]
  85. Taniuchi, K.; Nakagawa, H.; Hosokawa, M.; Nakamura, T.; Eguchi, H.; Ohigashi, H.; Ishikawa, O.; Katagiri, T.; Nakamura, Y. Overexpressed P-Cadherin/CDH3 Promotes Motility of Pancreatic Cancer Cells by Interacting with p120ctn and Activating Rho-Family GTPases. Cancer Res. 2005, 65, 3092–3099. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Jager, T.; Becker, M.; Eisenhardt, A.; Tilki, D.; Totsch, M.; Schmid, K.W.; Romics, I.; Rubben, H.; Ergun, S.; Szarvas, T. The prognostic value of cadherin switch in bladder cancer. Oncol. Rep. 2010, 23, 1125–1132. [Google Scholar] [CrossRef]
  87. Riener, M.-O.; Vogetseder, A.; Pestalozzi, B.C.; Clavien, P.-A.; Probst-Hensch, N.; Kristiansen, G.; Jochum, W. Cell adhesion molecules P-cadherin and CD24 are markers for carcinoma and dysplasia in the biliary tract. Hum. Pathol. 2010, 41, 1558–1565. [Google Scholar] [CrossRef] [PubMed]
  88. Bauer, R.; Valletta, D.; Bauer, K.; Thasler, W.E.; Hartmann, A.; Müller, M.; Reichert, T.E.; Hellerbrand, C. Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumorigenicity. Int. J. Clin. Exp. Pathol. 2014, 7, 6125–6132. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Cao, Z.-Q.; Wang, Z.; Leng, P. Aberrant N-cadherin expression in cancer. Biomed. Pharmacother. 2019, 118, 109320. [Google Scholar] [CrossRef]
  90. Saadatmand, S.; de Kruijf, E.M.; Sajet, A.; Dekker-Ensink, N.G.; van Nes, G.H.; Putter, H. Expression of cell adhesion molecules and prognosis in breast cancer. Br. J. Surg. 2013, 100, 252–260. [Google Scholar] [CrossRef]
  91. Drivalos, A.; Chrisofos, M.; Efstathiou, E.; Kapranou, A.; Kollaitis, G.; Koutlis, G.; Antoniou, N.; Karanastasis, D.; Dimopoulos, M.A.; Bamias, A. Expression of alpha5-integrin, alpha7-integrin, Epsilon-cadherin, and N-cadherin in localized prostate cancer. Urol. Oncol. 2016, 34, e11–e18. [Google Scholar] [CrossRef]
  92. Hui, L.; Zhang, S.; Dong, X.; Tian, D.; Cui, Z.; Qiu, X. Prognostic significance of twist and N-cadherin expression in NSCLC. PLoS ONE 2013, 23, e62171. [Google Scholar] [CrossRef] [Green Version]
  93. Muramaki, M.; Miyake, H.; Terakawa, T.; Kusuda, Y.; Fujisawa, M. Expression profile of E-cadherin and N-cadherin in urothelial carcinoma of the upper urinary tract is associated with disease recurrence in patients undergoing nephroureterectomy. Urology 2011, 78, e7–e12. [Google Scholar] [CrossRef]
  94. Seo, D.D.; Lee, H.C.; Kim, H.J.; Min, H.J.; Kim, K.M.; Lim, Y.S.; Chung, Y.H.; Lee, Y.S.; Suh, D.J.; Yu, E.; et al. Neural cadherin overexpression is a predictive marker for early postoperative recurrence in hepatocellular carcinoma patients. J. Gastroenterol. Hepatol. 2008, 23, 1112–1118. [Google Scholar] [CrossRef] [PubMed]
  95. Reginato, A.; Girolami, D.; Menchetti, L.; Foiani, G.; Mandara, M.T. E-cadherin, N-cadherin Expression and Histologic Characterization of Canine Choroid Plexus Tumors. Vet. Pathol. 2016, 53, 788–791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Buendia, A.J.; Peñafiel-Verdu, C.; Navarro, J.A.; Vilafranca, M.; Sanchez, J. N-cadherin Expression in Feline Mammary Tumors Is Associated with a Reduced E-cadherin Expression and the Presence of Regional Metastasis. Vet. Pathol. 2014, 51, 755–758. [Google Scholar] [CrossRef] [PubMed]
  97. Yan, X.; Yan, L.; Liu, S.; Shan, Z.; Tian, Y.; Jin, Z. N-cadherin, a novel prognostic biomarker, drives malignant progression of colorectal cancer. Mol. Med. Rep. 2015, 12, 2999–3006. [Google Scholar] [CrossRef] [Green Version]
  98. Lascombe, I.; Clairotte, A.; Fauconnet, S.; Bernardini, S.; Wallerand, H.; Kantelip, B.; Bittard, H. N-Cadherin as a Novel Prognostic Marker of Progression in Superficial Urothelial Tumors. Clin. Cancer Res. 2006, 12, 2780–2787. [Google Scholar] [CrossRef] [Green Version]
  99. Shimazui, T.; Kojima, T.; Onozawa, M.; Suzuki, M.; Asano, T.; Akaza, H. Expression profile of N-cadherin differs from other classical cadherins as a prognostic marker in renal cell carcinoma. Oncol. Rep. 2006, 15, 1181–1184. [Google Scholar] [CrossRef] [Green Version]
  100. Brunetti, B.; Sarli, G.; Preziosi, R.; Leprotti, S.; Benazzi, C. E-cadherin Expression in Canine Mammary Carcinomas with Regional Lymph Node Metastases. J. Vet. Med. Ser. A 2003, 50, 496–500. [Google Scholar] [CrossRef]
  101. De Matos, A.J.F.; Lopes, C.C.C.; Faustino, A.M.R.; Carvalheira, J.G.V.; Rutteman, G.R.; Gärtner, M.D.F.R.M. E-cadherin, β-catenin, invasion and lymph node metastases in canine malignant mammary tumours. APMIS 2007, 115, 327–334. [Google Scholar] [CrossRef]
  102. Li, Z.; Yin, S.; Zhang, L.; Liu, W.; Chen, B. Prognostic value of reduced E-cadherin expression in breast cancer: A meta-analysis. Oncotarget 2017, 8, 16445–16455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Kaszak, I.; Ruszczak, A.; Kanafa, S.; Kacprzak, K.; Król, M.; Jurka, P. Current biomarkers of canine mammary tumors. Acta Vet. Scand. 2018, 60, 66. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Gama, A.; Paredes, J.; Gärtner, F.; Alves, A.; Schmitt, F. Expression of E-cadherin, P-cadherin and β-catenin in canine malignant mammary tumours in relation to clinicopathological parameters, proliferation and survival. Vet. J. 2008, 177, 45–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Zuccari, D.A.P.C.; Pavam, M.V.; Terzian, C.B.; Pereira, R.S.; Ruiz, C.M.; Andrade, J.C. Immunohistochemical evaluation of e-cadherin, Ki-67 and PCNA in canine mammary neoplasias: Correlation of prognostic factors and clinical outcome. Pesqui. Vet. Bras. 2008, 28, 207–215. [Google Scholar] [CrossRef] [Green Version]
  106. Pires, I.; Queiroga, F.L.; Alves, A.; Silva, F.; Lopes, C. Decrease of E-Cadherin Expression in Canine Cutaneous Histiocytoma Appears to be Related to its Spontaneous Regression. Anticancer Res. 2009, 29, 2713–2717. [Google Scholar]
  107. Fonseca-Alves, C.E.; Rodrigues, M.M.P.; de Moura, V.M.B.D.; Rogatto, S.R.; Laufer-Amorim, R. Alterations of C-MYC, NKX3.1, and E-cadherin expression in canine prostate carcinogenesis. Micro Res. Tech. 2013, 76, 1250–1256. [Google Scholar] [CrossRef] [PubMed]
  108. Ramos-Vara, J.A.; Miller, M.A.; Gilbreath, E.; Patterson, J.S. Immunohistochemical Detection of CD34, E-cadherin, Claudin-1, Glucose Transporter 1, Laminin, and Protein Gene Product 9.5 in 28 Canine and 8 Feline Meningiomas. Vet. Pathol. 2010, 47, 725–737. [Google Scholar] [CrossRef]
  109. Munday, J.S.; Brennan, M.M.; Kiupel, M. Altered Expression of β-catenin, E-cadherin, Cycloxygenase-2, and p53 Protein by Ovine Intestinal Adenocarcinoma Cells. Vet. Pathol. 2006, 43, 613–621. [Google Scholar] [CrossRef]
  110. Zappulli, V.; De Cecco, S.; Trez, D.; Caliari, D.; Aresu, L.; Castagnaro, M. Immunohistochemical Expression of E-Cadherin and β-Catenin in Feline Mammary Tumours. J. Comp. Pathol. 2012, 147, 161–170. [Google Scholar] [CrossRef]
  111. Jolly, M.K.; Ware, K.E.; Xu, S.; Gilja, S.; Shetler, S.; Yang, Y.; Wang, X.; Austin, R.G.; Runyambo, D.; Hish, A.J.; et al. E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms. Mol. Cancer Res. 2019, 17, 1391–1402. [Google Scholar] [CrossRef] [Green Version]
  112. Bendardaf, R.; Sharif-Askari, F.S.; Sharif-Askari, N.S.; Syrjanen, K.; Pyrhonen, S. Cytoplasmic E-Cadherin Expression Is Associated with Higher Tumour Level of VEGFA, Lower Response Rate to Irinotecan-based Treatment and Poorer Prognosis in Patients with Metastatic Colorectal Cancer. Anticancer Res. 2019, 39, 1953–1957. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Canadas, A.; Santos, M.; Medeiros, R.; Dias-Pereira, P. Influence of E-cadherin genetic variation in canine mammary tumour risk, clinicopathological features and prognosis. Vet. Comp. Oncol. 2019, 17, 489–496. [Google Scholar] [CrossRef]
  114. Pal, M.; Bhattacharya, S.; Kalyan, G.; Hazra, S. Cadherin profiling for therapeutic interventions in Epithelial Mesenchymal Transition (EMT) and tumorigenesis. Exp. Cell Res. 2018, 368, 137–146. [Google Scholar] [CrossRef] [PubMed]
  115. Shen, K.-H.; Liao, A.C.-H.; Hung, J.-H.; Lee, W.-J.; Hu, K.-C.; Lin, P.-T.; Liao, R.-F.; Chen, P.-S. α-Solanine inhibits invasion of human prostate cancer cell by suppressing epithelial-mesenchymal transition and MMPs expression. Molecules 2014, 19, 11896–11914. [Google Scholar] [CrossRef] [PubMed]
  116. Xie, F.; Liu, J.; Li, C.; Zhao, Y. Simvastatin blocks TGF-β1-induced epithelial-mesenchymal transition in human prostate cancer cells. Oncol. Lett. 2016, 11, 3377–3383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Zhang, J.; Shen, C.; Wang, L.; Ma, Q.; Xia, P.; Qi, M.; Yang, M.; Han, B. Metformin inhibits epithelial-mesenchymal transition in prostate cancer cells: Involvement of the tumor suppressor miR30a and its target gene SOX4. Biochem. Biophys. Res. Commun. 2014, 452, 746–752. [Google Scholar] [CrossRef]
  118. Blaschuk, O.W. N-cadherin antagonists as oncology therapeutics. Philos. Trans. R Soc. Lond. B Biol. Sci. 2015, 370, 20140039. [Google Scholar] [CrossRef] [Green Version]
  119. Williams, E.; Williams, G.; Gour, B.J.; Blaschuk, O.W.; 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, 4007–4012. [Google Scholar] [CrossRef] [Green Version]
  120. Shintani, Y.; Fukumoto, Y.; Chaika, N.; Grandgenett, P.M.; Hollingsworth, M.A.; Wheelock, M.J.; Johnson, K.R. ADH-1 suppresses N-cadherin-dependent pancreatic cancer progression. Int. J. Cancer 2008, 122, 71–77. [Google Scholar] [CrossRef]
  121. Perotti, A.; Sessa, C.; Mancuso, A.; Noberasco, C.; Cresta, S.; Locatelli, A.; Carcangiu, M.L.; Passera, K.; Braghetti, A.; Scaramuzza, D.; et al. Clinical and pharmacological phase I evaluation of Exherin™ (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours. Ann. Oncol. 2009, 20, 741–745. [Google Scholar] [CrossRef]
  122. Devemy, E.; Blaschuk, O.W. Identification of a novel N-cadherin antagonist. Peptides 2008, 29, 1853–1861. [Google Scholar] [CrossRef] [PubMed]
  123. Liu, J.; Sun, X.; Qin, S.; Wang, H.; Du, N.; Li, Y.; Pang, Y.; Wang, C.; Xu, C.; Ren, H. CDH1 promoter methylation correlates with decreased gene expression and poor prognosis in patients with breast cancer. Oncol. Lett. 2016, 11, 2635–2643. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Wu, X.; Yao, X.; Cao, Q.; Wu, Z.; Wang, Z.; Liu, F.; Shen, L. Clinicopathological and prognostic significance of CDH1 hypermethylation in hepatocellular carcinoma: A meta-analysis. Cancer Manag. Res. 2019, 11, 857–864. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Buda, A.; Pignatelli, M. E-Cadherin and the Cytoskeletal Network in Colorectal Cancer Development and Metastasis. Cell Commun. Adhes. 2011, 18, 133–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Gregory, D.J.; Mikhaylova, L.; Fedulov, A.V. Selective DNA demethylation by fusion of TDG with a sequence-specific DNA-binding domain. Epigenetics 2012, 7, 344–349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Battistini, C.; Rehman, M.; Avolio, M.; Arduin, A.; Valdembri, D.; Serini, G.; Tamagnone, L. Rhomboid-Like-2 Intramembrane Protease Mediates Metalloprotease-Independent Regulation of Cadherins. Int. J. Mol. Sci. 2019, 20, 5958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Herbst, A.; Kolligs, F.T. Wnt Signaling as a Therapeutic Target for Cancer. In Target Discovery and Validation Reviews and Protocols: Volume 2: Emerging Molecular Targets and Treatment Options; Sioud, M., Ed.; Humana Press: Totowa, NJ, USA, 2007; pp. 63–91. [Google Scholar] [CrossRef]
  129. Liu, L.X.; Lee, N.P.; Chan, V.W.; Xue, W.; Zender, L.; Zhang, C.; Mao, M.; Dai, H.; Wang, X.L.; Xu, M.Z. Targeting cadherin-17 inactivates Wnt signaling and inhibits tumor growth in liver carcinoma. Hepatology 2009, 50, 1453–1463. [Google Scholar] [CrossRef]
  130. Ciołczyk-Wierzbicka, D.; Laidler, P. The inhibition of invasion of human melanoma cells through N-cadherin knock-down. Med. Oncol. (Northwood Lond. Engl.) 2018, 35, 42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Li, K.; He, W.; Lin, N.; Wang, X.; Fan, Q.-X. N-cadherin knock-down decreases invasiveness of esophageal squamous cell carcinoma in vitro. World J. Gastroenterol. 2009, 15, 697–704. [Google Scholar] [CrossRef]
Figure 1. Scheme of the cadherin-catenin complex based on Gama et al. 2012 [29]. Cadherins have extracellular domain, transmembrane domain and a cytoplasmic tail. These transmembrane domains are composed of five cadherin repeats and are responsible for calcium dependent cell-cell adhesion. The cytoplasmic tail is composed of a juxtamembrane domain (proximal to the plasma membrane), which binds to p120-catenin, and a catenin-binding domain, which binds to β-catenin. β-catenin binds to α-catenin, which links cadherins to the actin cytoskeleton.
Figure 1. Scheme of the cadherin-catenin complex based on Gama et al. 2012 [29]. Cadherins have extracellular domain, transmembrane domain and a cytoplasmic tail. These transmembrane domains are composed of five cadherin repeats and are responsible for calcium dependent cell-cell adhesion. The cytoplasmic tail is composed of a juxtamembrane domain (proximal to the plasma membrane), which binds to p120-catenin, and a catenin-binding domain, which binds to β-catenin. β-catenin binds to α-catenin, which links cadherins to the actin cytoskeleton.
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Figure 2. Common signaling pathways of epithelial-to-mesenchymal transition based on Albrecht et al. [80]. Snail and Slug regulate “cadherin switch” by downregulating E-cadherin (E-cad) and inducing the expression of mesenchymal neuronal-cadherin (N-cad). Signaling pathways such as Wnt and TGF-β activate SNAIL and SLUG. N-cad stimulates cell proliferation through mitogen activated protein kinase (MAPK) pathways. The loss of E-cad can also result in the mislocalization of α-catenin and p120 catenin, which leads to the activation of MAPK pathways. Somatic mutations of E-cad leading to its downregulation disrupt normal signaling to Rho GTPases (Rac1 and RhoA), which leads to tumor cell migration and invasion. Upregulated placental-cadherin (P-cad) induces the insulin-like growth factor 1 receptor (IGF-1R) signaling pathway, which also leads to Rho GTPase signaling that promotes migration and invasion.
Figure 2. Common signaling pathways of epithelial-to-mesenchymal transition based on Albrecht et al. [80]. Snail and Slug regulate “cadherin switch” by downregulating E-cadherin (E-cad) and inducing the expression of mesenchymal neuronal-cadherin (N-cad). Signaling pathways such as Wnt and TGF-β activate SNAIL and SLUG. N-cad stimulates cell proliferation through mitogen activated protein kinase (MAPK) pathways. The loss of E-cad can also result in the mislocalization of α-catenin and p120 catenin, which leads to the activation of MAPK pathways. Somatic mutations of E-cad leading to its downregulation disrupt normal signaling to Rho GTPases (Rac1 and RhoA), which leads to tumor cell migration and invasion. Upregulated placental-cadherin (P-cad) induces the insulin-like growth factor 1 receptor (IGF-1R) signaling pathway, which also leads to Rho GTPase signaling that promotes migration and invasion.
Ijms 21 07624 g002
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Kaszak, I.; Witkowska-Piłaszewicz, O.; Niewiadomska, Z.; Dworecka-Kaszak, B.; Ngosa Toka, F.; Jurka, P. Role of Cadherins in Cancer—A Review. Int. J. Mol. Sci. 2020, 21, 7624. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207624

AMA Style

Kaszak I, Witkowska-Piłaszewicz O, Niewiadomska Z, Dworecka-Kaszak B, Ngosa Toka F, Jurka P. Role of Cadherins in Cancer—A Review. International Journal of Molecular Sciences. 2020; 21(20):7624. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207624

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Kaszak, Ilona, Olga Witkowska-Piłaszewicz, Zuzanna Niewiadomska, Bożena Dworecka-Kaszak, Felix Ngosa Toka, and Piotr Jurka. 2020. "Role of Cadherins in Cancer—A Review" International Journal of Molecular Sciences 21, no. 20: 7624. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207624

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