Soluble N‐cadherin in human biological fluids

Abstract

Classical cadherins such as E-, P-and N-cadherin are transmembrane proteins that mediate cell-cell adhesion, and are important in embryogenesis, maintenance of tissue integrity and cancer. Proteolytic shedding of the extracellular domain results in the generation of soluble E-, P-or N-cadherin ectodomains. Circulating soluble E-and P-cadherin have been described in the serum, and elevated levels were detected in cancer patients when compared with healthy persons. Here we report the presence of soluble N-cadherin, a 90-kD protein fragment, in the serum of both healthy persons and cancer patients, using a direct ELISA and immunoprecipitation. A correlation was found between prostate specific antigen and soluble N-cadherin, and significantly elevated levels were detected in prostate cancer follow-up patients. The Ncadherin protein is neo-expressed by carcinomas of the prostate, and is responsible for epithelial to fibroblastic transition. This is reflected by the higher concentrations of soluble N-cadherin in prostate cancer patients than in healthy persons. ' 2006 Wiley-Liss, Inc.Key words: soluble N-cadherin; serum; cancer Cell-cell adhesion molecules play an important role during embryogenesis, tumor invasion and metastasis. The cadherins, Ca 21 -dependent cell-cell adhesion molecules, are essential for intercellular connections. E (epithelial)-cadherin is involved in normal epithelial cell-cell interactions, but is often downregulated in epithelioid cancer cells. These cancer cells can switch cadherin expression from E-to N-(neural), 1 E-to P-(placental) 2 or E-to OB-(osteoblast)-cadherin.3 This coincides with the transition from an epithelioid to a fibroblastic phenotype, and is often correlated with invasiveness. 4 Proteolysis can contribute to the impairment of the cadherin function. Several enzymes have been shown to be responsible for the shedding of the extracellular domain. Cleavage of E-cadherin and shedding of an 80-kD fragment can be mediated by matrilysin, stromelysin-1, 5,6 plasmin 7 and a disintegrin and metalloproteinase 10 (ADAM10).8 For N-cadherin, a 90-kD fragment can be released by the enzymes matrix metalloproteinase (MMP), 9 plasmin, 10 ADAM10, 11 membrane type 1-MMP (MT1-MMP) 12 and MT5-MMP. 13Soluble E-cadherin (sE-CAD) has been described in the circulation of cancer patients.14 In that study, the mean sE-CAD level, detected by enzyme linked immunosorbent assay (ELISA), in serum was significantly higher in the studied cancer patients (3.8 6 2.36 lg/ml) when compared with the healthy controls (1.99 6 0.5 lg/ml). In addition, sE-CAD was detected in serum of patients with diabetes or hepatitis, but these values were not significantly different from the healthy controls. As a result, sE-CAD is now propagated as a marker for early prediction of tumor recurrence of gastric cancer.15 sE-CAD is also found in urine 16 and the mean levels in the urine of patients with bladder cancer are significantly higher than in the urine of healthy persons (1.6 vs. 0.9 lg/ml). 17High levels of sE-CAD appear to ...

A Switch from E-Cadherin to N-Cadherin Expression Indicates Epithelial to Mesenchymal Transition and Is of Strong and Independent Importance for the Progress of Prostate Cancer

“…Thus, cell adhesion molecules might add prognostic information beyond that presently given by histologic evaluation alone (44). Supporting our findings, soluble E-cadherin and N-cadherin were recently studied as serum biomarkers in prostate cancer, suggesting increased level of N-cadherin as a marker of ongoing EMT and tumor progress (45,46). The higher frequency of positive N-cadherin staining compared with two other studies (11,12) may be a result of increased detection using a different antibody validated by Western blot (35) in our lab.…”

ADAM15 Supports Prostate Cancer Metastasis by Modulating Tumor Cell–Endothelial Cell Interaction

“…The loss of full-length N-cadherin reduces cell adhesion and may promote cell migration (44). Furthermore, serum levels of soluble N-cadherin are upregulated in multiple cancers including prostate cancer and correlated directly with an increase in PSA levels (45). Within our current study, we have made the interesting observation that shADAM15 PC-3…”

Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression

“…In contrast, markers of a mesenchymal phenotype including N-cadherin, OB (osteoblast)-cadherin, and WAP-type four disulfide core/ps20 proteins (WFDC-1) are all upregulated by tumor cells (Tomita et al, 2000;McAlhany et al, 2004;Jaggi et al, 2006). Increased levels of the extracellular domain of N-cadherin have also been detected in the serum of prostate cancer patients (Derycke et al, 2006). Importantly, the functional importance of decreased E-cadherin levels has also been demonstrated in prostate cancer cells with its inverse correlation with cellular motility and protease expression (Chunthapong et al, 2004).…”