Expression of epithelial–mesenchymal transition markers in renal cell carcinoma: impact on prognostic outcomes in patients undergoing radical nephrectomy

Abstract

What's known on the subject? and What does the study add?There have been few studies evaluating the prognostic value of epithelial‐mesenchymal transition markers in renal cell carcinoma (RCC); therefore, the significance of these markers in the prognosis of patients with RCC, particularly that in those with localized disease, remains largely unknown.Consideration of the expression levels of potential epithelial‐mesenchymal transition markers, particularly clusterin and Twist in addition to conventional prognostic parameters, would contribute to the prediction of disease recurrence after radical nephrectomy for localized renal cell carcinoma.OBJECTIVE To evaluate the expression of multiple molecular markers involved in the process of epithelial–mesenchymal transition (EMT) in renal cell carcinoma (RCC) with the aim of clarifying the prognostic significance of these markers in patients undergoing radical nephrectomy. PATIENTS AND METHODS The expression levels of 11 EMT markers, including E‐cadherin, N‐cadherin, β‐catenin, γ‐catenin, clusterin, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in radical nephrectomy specimens from 122 patients with clinically localized RCC were measured by immunohistochemical staining. RESULTS In this series, disease recurrence occurred in 39 (32.0%) patients, with a 5‐year recurrence‐free survival rate of 64.4%. Univariate analysis identified expression levels of E‐cadherin, clusterin, Twist and vimentin, in addition to C‐reactive protein (CRP) level, pathological stage and microvascular invasion, as significant predictors for disease recurrence. Of these, expression levels of clusterin and Twist, CRP levels and microvascular invasion appeared to be independently related to disease recurrence on multivariate analysis. There were significant differences in recurrence‐free survival according to positive numbers of these four independent factors: disease recurrence occurred in two of 26 patients negative for any risk factor (7.7%), 23 of 73 pateints positive for one or two risk factors (31.5%) and 14 of 23 patients positive for three or four risk factors (60.9%). CONCLUSION Consideration of the expression levels of potential EMT markers, particularly clusterin and Twist, in RCC specimens, in addition to conventional prognostic parameters, contributes to the accurate prediction of disease recurrence after radical nephrectomy for localized RCC.

Impact of E-Cadherin and β-Catenin as Prognostic Factor in Renal Cell Carcinoma with Tumor Thrombus of the Vena Cava

“…The prognostic role of β-Catenin expression in RCC is controversial. Krabbe et al [18] could identify an association between reduced β-Catenin-expression and worse RFS and CSS, whereas there are several studies showing no association between β-Catenin-expression and survival [26,28]. Furthermore, there are several studies suggesting a worse prognostic effect of high cytoplasmic β-Catenin expression and worse survival [15,21,22].…”

“…It could be shown that high β-Cateninexpression is associated with higher grading [15] and advanced stage, vascular invasion, and tumor necrosis [21]. However, other studies could not prove the correlation with adverse clinical and pathological parameters [18,26,28]. On a functional level, stabilization and thus high β-Catenin-expression promotes cell proliferation, migration, and invasion in RCC [19,20].…”

“…Furthermore, some authors could also find a relationship between reduced E-cadherin expression and worse CSS [15,16] or RFS [26]. In some studies, no association between E-cadherin-expression and survival could be found [27].…”

“…Mikami et al [27] could show that more E-cadherin-expressing tumors could be found in higher stages (pT3/4), lymph node metastasis, and higher graded tumors (G3), also indicating to the presence of more aggressive and invasive tumors. However, no correlation between E-cadherin-expression and grading and staging [16,26] or distant metastasis [16] could be found, so the role of E-cadherin-expression in RCC still remains unclear.…”

Epithelial to Mesenchymal Transition in Clear Cell Renal Cell Carcinoma with Rhabdoid Features

“…They evaluated the membranous immunoexpression of E-cadherin, the cytoplasmic immunoexpression of vimentin, and the nuclear immunoexpression of Snail, Slug, ZEB1, ZEB2 and Twist1. We performed a semiquantitative estimation based on the intensity and extent of stained cells for each case, as previously described [22,23]. The staining intensity was graded from 0 to 3 (0  =  no staining at all, 1  =  weak, 2  =  moderate, 3  = strong).…”