Schematic overview of representative human members of the cadherin superfamily with reported involvement in cancer (modified after Hulpiau and van Roy 2009).
All proteins are drawn to scale and aligned at their transmembrane domain (TM).
Perspectives for emerging cadherin-related anticancer therapies are given.
Cell–cell adhesion determines cell polarity and participates in cell differentiation and in establishment and maintenance of tissue homeostasis.
Epithelial tumors often lose E-cadherin partially or completely as they progress toward malignancy (reviewed by Birchmeier and Behrens 1994; Christofori and Semb 1999; Strumane et al. Epithelial ovarian cancers are exceptional because expression of E-cadherin in inclusion cysts, derived from ovarian surface epithelium with little or no E-cadherin, appears to be essential for tumorigenesis in this organ (Sundfeldt 2003; Naora and Montell 2005). However, most studies have shown both strong anti-invasive and antimetastatic roles for E-cadherin (Frixen et al. 3), leading to inhibition of its function in the canonical Wnt pathway (Fig.
Another exception is inflammatory breast cancer, a distinct and aggressive form of breast cancer in which the expression of E-cadherin is consistently elevated regardless of the histologic type or molecular profile of the tumor (Table 1) (Alpaugh et al. 4), besides inhibition of EGF receptor signaling and contribution to epithelial apico-basal polarization. This region frequently shows loss of heterozygosity (LOH) in different human carcinoma types.
Most human tumors are carcinomas derived from epithelial tissues, in which E-cadherin is the prototypic cadherin. 2008), include the sequestering of β-catenin in an E-cadherin-catenin adhesion complex (Fig.Three cell types are partly depicted: a cancer cell, an endothelial cell, and another type of stromal cell. Several other proteases, such as the serine protease kallikrein 6 (Klk6), are up-regulated in human squamous skin carcinomas. In human prostate cancers, cadherin-11 expression increases with progression from primary to metastatic disease in lymph nodes and particularly in bone (Chu et al. E-cadherin repressors, such as Snail, ZEB2/SIP1, and Slug, can induce N-cadherin and cadherin-11 expression during EMT, suggesting that this cadherin switch is part of a transcriptional reprogramming of dedifferentiating epithelial cells (Cano et al. This reprogramming and differentiation of endothelial cells accompanies loss of endothelial barrier function and vascular leakage, which could be relevant during Kaposi's sarcoma tumor formation (Mansouri et al. Antiangiogenic tumor therapy is lately receiving much attention in the form of anti-VEGF therapy (Loges et al. Also VE-cadherin has become a target for inhibition of pathological angiogenesis. Specificity for angiogenic tumor vasculature was further enhanced by targeting a VE-cadherin epitope that is at least partly engaged in trans-dimer formation, and thus is masked on established vessels (May et al. This therapy is antiangiogenic during neovascularization because de novo adherens junction formation is inhibited.Protein domains in green are strongly homologous to those in the prototypic E-cadherin/CDH1. Ectopic expression of Klk6 in keratinocytes induces E-cadherin ectodomain shedding in parallel with increased levels of mature ADAM10 proteinase (Klucky et al. Pancreatic adenocarcinomas often overexpress kallikrein-7, which can also generate soluble E-cadherin fragments that may function as pseudoligands to block normal E-cadherin interactions and promote invasion (Johnson et al. In epithelial ovarian carcinomas, the tumor cells maintain direct contact with ascites, which accumulates high concentrations of the solubilized E-cadherin ectodomain, and thereby promotes disruption of cell–cell junctions and metastatic dissemination (Symowicz et al. ADAM15, which is associated with progression of breast and prostate cancers, also generates a soluble E-cadherin ectodomain (Najy et al. This E-cadherin fragment appeared to stabilize heterodimerization of the HER2 (Erb B2) receptor tyrosine kinase with HER3, thus leading to Erk signaling, which stimulates both cell proliferation and migration. Manipulation of cadherin-11 expression in experimental metastasis models for breast and prostate cancers suggests that it promotes homing and migration to bone (Chu et al. Monoclonal antibodies directed against VE-cadherin could inhibit angiogenesis and reduce tumor growth of experimental hemangiomas and gliomas (Corada et al. The potential value of anti-VE-cadherin therapy was further shown by using a cyclic peptide directed against VE-cadherin to inhibit oxygen-induced retinal neovascularization (Navaratna et al. Regarding angiogenesis, it is worth mentioning that endothelial cells also express N-cadherin, R-cadherin (CDH4), and T-cadherin (cadherin-13; see the following discussion).The atypical T-cadherin/CDH13 is often silenced in cancer cells but up-regulated in tumor vasculature.The review also covers the status of protocadherins and several other cadherin-related molecules in human cancer.The latter induce epithelial mesenchymal transition, which is also associated with induction of “mesenchymal” cadherins, a hallmark of tumor progression.