Expression of e-cadherin and α-, β-, γ-catenins in patients with bladder cancer : Identification of γ-catenin as a new prognostic marker of neoplastic progression in T1 superficial urothelial tumors

Loss of intercellular adhesion facilitates tumor invasion. To clarify the relation between altered expression of cell adhesion molecules and progression of T1 superficial bladder tumors, 101 cases (71 T1 tumors, 30 T2/T3 tumors) were examined immunohistochemically for E-cadherin and α-, β-, and γ-catenins. A highly significant correlation was observed between the decreased expression of all molecules and increased TNM stage (P < .001). Univariate analysis, performed in cases of T1 tumors, revealed association of abnormal E-cadherin with βcatenin diminution. Survival curves were established with the Kaplan-Meier method and analyzed according to clinical and histopathologic parameters using the log-rank test. Cox multivariate analysis revealed only γcatenin as an independent predictor of progression-free survival in patients with stage T1 bladder urothelial tumors. The characterization of T1 tumors that will progress could lead to the identification of patients who might benefit from surgery to avoid vesical muscle invasion and, consequently, metastasis. Urothelial carcinoma is the most common solid malignancy of the bladder. It is distinguished as muscle-invasive carcinoma or superficial bladder tumor. Muscle-invasive carcinomas generally are associated with poor prognosis, whereas the clinical outcome of superficial bladder tumors is relatively unpredictable. The recurrence rate of T1 superficial bladder tumors is high (80%), and 40% of them will progress to a poorer prognosis muscle-invasive disease. Stage and grade, based on histopathologic criteria, are classic prognostic variables that permit evaluating recurrence or progression of the disease, which is useful for clinical purposes. 1 The identification of new prognostic markers allowing improvement of the biologic assessment of the T1 superficial tumors could be of great clinical value for disease management. Tumor progression is accompanied by altered expression of cell adhesion molecules such as cadherins. E-cadherin, one subtype of transmembrane glycoprotein that mediates calciumdependent adhesion of cells, is expressed specifically in epithelia and is involved in maintenance of their phenotype. Its cytoplasmic domain associates with cytoplasmic proteins termed catenins. βCatenin or γ-catenin binds directly, whereas α-catenin links the bound β-catenin or γ-catenin to the actin microfilament network of the cellular cytoskeleton. This binding is essential for stable cell-to-cell adhesion. 2 Reduction in expression of these molecules has been reported in human cancers. 3-5 In the bladder, studies have shown that decreased E-cad