Alterations in cadherin and catenin expression during the biological progression of melanocytic tumours

Abstract

Aims-Compelling evidence from cell culture studies implicates cadherins in the neoplastic progression of melanocytic tumours but few reports describe the expression of cadherins and the related transmembrane proteins, catenins, in a full range of benign and malignant excised melanocytic tumours. Methods-Using immunohistochemistry and western blotting after tissue fractionation, the pattern of expression of cadherins/ catenins was studied in a range of surgically excised melanocytic tumours, from dysplastic naevi to stage III cutaneous metastatic malignant melanoma. Results-Appropriate membranous expression of E-cadherins and P-cadherins is seen in dysplastic naevocytes with an epithelioid phenotype and is largely maintained with malignant transformation to radial growth phase melanoma and primary vertical growth phase malignant melanoma.Loss of membranous E-cadherin is seen in a small number of vertical growth phase melanomas only when metastasis has occurred. However, there is a concomitant dramatic loss of membranous P-cadherin expression in all melanomas at the same stage. A minority of metastatic melanomas show de novo membranous N-cadherin expression in comparison with dysplastic naevi and primary melanoma. Membranous expression of the desmosomal cadherin, desmoglein, was not seen in any tumour studied. Frequently, catenin is aberrantly produced in the cytoplasm of cells in dysplastic naevi and metastatic malignant melanoma, with an implied compromise to adhesive function. Furthermore, membranous catenin expression was not seen in any of the 70 melanocytic tumours studied, implying obligatory transmembrane binding of cadherins to catenin for maintenance of adhesive function. Conclusions-The most important alterations in membranous cadherin and catenin expression are seen late in the biological progression of melanocytic tumours at the stage of "in transit" or regional lymph node metastasis, with implications for tumour growth, invasion, and dissemination. (J Clin Pathol: Mol Pathol 1999;52:151-157)

Prognostic Significance of Cadherin-Based Adhesion Molecules in Cutaneous Malignant Melanoma

“…In accordance with data published by Sanders et al (24), we have shown that P-cadherin and h-catenin have extremely similar expression profiles through Spearman correlation coefficients and a dendrogram after hierarchical clustering. According to our data, p120-catenin and a-catenin also share similarity to the former proteins.…”

“…This same study reported no association between either p120-catenin or g-catenin with both Breslow thickness and tumor status (23). One other study attempted to investigate g-catenin but could not detect this marker in their immunohistochemical assay (24).…”

Loss of E-cadherin Expression in Melanoma Cells Involves Up-regulation of the Transcriptional Repressor Snail

“…Immunohistochemical studies of E-cadherin expression in malignant melanomas demonstrated significant down-regulation of E-cadherin in the tumor tissue compared with benign melanocytes and melanocytic nevi (4,5). Evidence for the functional relevance of this phenomenon was obtained by Herlyn and co-workers (19 -21), who showed that down-regulation of E-cadherin leads to deregulated control of melanocyte proliferation by keratinocytes and in parallel to an invasive growth behavior.…”

Loss of E-cadherin leads to upregulation of NFκB activity in malignant melanoma

“…Owing to its critical function in intercellular adhesion, E-cadherin has also been assumed to act as a tumor suppressor negatively regulating several critical steps of invasion and metastasis. Loss of E-cadherin expression during tumor development was recently observed in a variety of different tumor types including malignant melanomas (Berx et al, 1995(Berx et al, , 1996Tamura et al, 1996a, b;Silye et al, 1998;Sanders et al, 1999;Melki et al, 2000;Poser et al, 2001). Further, we have shown that inhibition of the expression of the transcriptional repressor snail induced re-expression of Ecadherin in Mel Im melanoma cells (Poser et al, 2001).…”