ERG and nestin: useful markers of immature vessels and novel prognostic markers in renal cell carcinoma

Abstract

Objectives: Renal cell carcinoma (RCC) accounts for approximately 90% of all renal malignancy. Because a rich vasculature is an outstanding feature of RCC, information on the blood vessels of RCC might explain its tumor characteristics. Several researchers have noted the effects of tumor vessels on the clinicopathologic characteristics and prognosis of tumors; however, a clear association has not been established. We hypothesized that the immaturity of the neovasculature may be an important clinicopathologic characteristic forprognosis of RCC patients. ERG and nestin are new vascular markers that regulate vascular homeostasis and angiogenesis. Therefore, in the present study, we investigated how ERG and nestin were expressed with respect to tumor characteristics.

Materials and methods: IHC staining for ERG, nestin, CD31, and CD34 was performed for 217 renal tumors, including clear-cell RCC (ccRCC; n = 184), papillary RCC (pRCC; n = 14), chromophobe RCC (chRCC; n = 14), and oncocytoma (n = 5).

Results: Vascular endothelial cells from normal kidney consistently showed strong nuclear expression of ERG and nestin. Conversely, a loss of ERG and nestin expression was observed in endothelial cells of some tumor blood vessels, which was associated with tumor progression. In particular, the loss of ERG expression was significantly associated with progression-free survival and overall survival (univariate analyses: P = 0.027 and P = 0.004, respectively; multivariate analyses: P = 0.030 and P = 0.046, respectively).

Conclusion: A loss of ERG and nestin expression is associated with tumor progression, and loss of ERG is a powerful prognostic marker for ccRCC.

Keywords: ERG; Renal cell carcinoma; angiogenesis; immature vessel; nestin; prognostic factor.

Figure 1

Erythroblast transformation-specific-related gene (ERG) expression (magnification 200×). (A) Negative expression of ERG in clear-cell renal cell carcinoma (ccRCC); normal vessel shows positive ERG expression in the lower right corner, (B) equivocal expression of ERG in ccRCC, (C) positive expression of ERG in ccRCC, (D) expression of ERG in normal kidney cortex, (E) negative expression of nestin in ccRCC, (F) equivocal expression of nestin in ccRCC, (G) positive expression of nestin in ccRCC, (H) expression of nestin in normal kidney cortex, (I) negative expression of ERG in chromophobe RCC, (J) no loss of the expression of ERG in oncocytoma.

Figure 2

A. Kaplan Meier survival curve for progression-free survival. Kaplan Meier analysis shows decreased progression-free survival in the ERG negative group vs. ERG positive group. *Log rank test P = 0.064. ^†Negative vs. positive post hoc analysis, raw P = 0.027. B. Kaplan Meier survival curve for overall survival (OS). Kaplan Meier analysis shows decreased OS in the ERG negative group vs. ERG positive group. *Log rank test P = 0.0042. Negative vs. positive post hoc analysis, raw P = 0.004.