E- to N-cadherin switch in melanoma is associated with decreased expression of phosphatase and tensin homolog and cancer progression

摘要

Background Cadherin switch in melanoma, with loss of E-cadherin and upregulation of N-cadherin, is believed to underlie melanoma cell detachment from the epidermis and promotion of dermal and vascular melanoma invasion. The tumour suppressor phosphatase and tensin homolog (PTEN) has been suggested as a potential regulator of this cadherin switch. Objectives To study the biological and clinical implications of cadherin switch and PTEN expression in melanoma progression. Methods We constructed tissue microarrays from primary tumour samples from 394 formalin-fixed paraffin-embedded melanomas diagnosed between 2001 and 2006. Median follow-up was 10 years. Tissue microarray sections were stained by immunohistochemistry for E-cadherin, N-cadherin and PTEN, and expression was analysed semiquantitatively. Results Breslow thickness correlated strongly with reduced/absent PTEN expression (P < 0·0001), low E-cadherin expression (P < 0·0001), high N-cadherin expression (P < 0·0001) and the combination of low E-cadherin and high N-cadherin expression (cadherin switch profile; P = 0·001). There was a significant association between reduced/absent PTEN and the presence of the cadherin switch profile (P = 0·03). In univariate analyses, low E-cadherin expression significantly predicted an adverse overall relapse-free (P = 0·04), melanoma-specific (P = 0·03) and distant-metastasis-free (P = 0·01) survival; reduced/absent PTEN predicted an adverse overall relapse-free survival (P = 0·006), and the cadherin switch profile predicted adverse melanoma-specific (P = 0·005) and distant-metastasis- free (P = 0·01) survival. In multivariate analysis, the cadherin switch profile was an independent prognostic marker of melanoma-specific (P = 0·04) and distant-metastasis-free survival (P = 0·02). Conclusions Cadherin switch and reduced/absent PTEN expression are associated in melanoma, and both factors may play important roles in the progression of melanoma. What's already known about this topic? Downregulation of E-cadherin and upregulation of N-cadherin (cadherin switch) has been associated with melanoma progression. Cadherin switching has been associated with a downregulation of phosphatase and tensin homolog (PTEN). Large clinical studies on the combinations of cadherin expression profiles and PTEN are sparse. What does this study add? In a large melanoma cohort we demonstrated that a reduced/absent expression of PTEN is associated with a cadherin switch profile. This in turn is associated with increasing primary tumour thickness. The cadherin switch profile is an independent prognostic marker of distant metastases and death from melanoma.