Imbalance between Neutral Endopeptidase 24.11 and Endothelin-1 Expression in Human Endometrial Carcinoma

Abstract

Objectives: Neutral endopeptidase 24.11 (NEP)/CD10 is a cell-surface peptidase that degrades various bioactive peptides including endothelin-1 (ET-1). This enzyme is known to play a role in maintaining ET-1-regulated vascular homeostasis in the normal human endometrium. The purpose of the present study was to investigate the expression and localization of NEP and ET-1 in neoplastic endometria, and also to clarify the correlation of their expression with the tumor grade of endometrial carcinoma. Methods: Immunohistochemical analysis for NEP and ET-1 expression was performed on paraffin-embedded tissue sections of 7 normal endometria (after menopause), 5 atypical endometrial hyperplasias (AEH), and 32 endometrial endometrioid adenocarcinomas. Results: In normal endometrium and AEH, NEP immunoreactivity was detected in stromal cells, but not in glandular cells. In contrast, ET-1 immunoreactivity was detected in both glandular and stromal cells. In the stromal cells of grade 1 endometrial adenocarcinoma, NEP was detected at high or moderate quantities. However, significantly decreased NEP immunoreactivity was observed in the stromal cells of grade 2 and 3 adenocarcinomas. However, NEP was not immunostained in adenocarcinoma cells except for the lesions of squamous differentiation. ET-1 immunoreactivity was weakly detected in the stromal cells of grade 1 adenocarcinoma, but the intensity of ET-1 staining increased with advancing tumor grade. The ratio of the staining scores of stromal ET-1 to stromal NEP was positively correlated with the tumor grade. Conclusions: These findings demonstrate that NEP expression in the stromal cells of endometrial adenocarcinoma is downregulated, while stromal ET-1 is upregulated, with increasing tumor grade. The present findings also suggest that NEP may play a role in the regulation of neoplastic transformation, tumor progression, and differentiation in endometrial neoplasms, possibly by degrading certain peptide growth factors such as ET-1.

Stromal–epithelial interactions influence prostate cancer cell invasion by altering the balance of metallopeptidase expression

“…This correlation in PC cells of loss of NEP expression and cell migration is explained by the catalytic capability of NEP to inactivate mitogenic peptides such as ET-1 and bradykinin which promote cell migration. This is consistent with the findings of Suzuki et al (2001) in human endometrial cancer.…”

Neutral Endopeptidase 24.11/CD10 Suppresses Progressive Potential in Ovarian Carcinoma In vitro and In vivo

“…NEP was also reported to be involved in carcinoma cell differentiation and apoptosis by regulating the local concentration of possible bioactive peptides including ET-1 (13,23). In ovarian carcinoma, our previous reports showed that NEP was specifically expressed in the stroma of borderline and malignant ovarian tumors but not in benign adenomas and that stromal NEP expression was down-regulated as the histologic grade advanced (20).…”

Expression of Placental Leucine Aminopeptidase Is Associated with a Poor Outcome in Endometrial Endometrioid Adenocarcinoma

“…The possible involvement of several cell-surface aminopeptidases, such as neutral endopeptidase (CD10), dipeptidyl peptidase IV (DPPIV, CD26) and aminopeptidase A, has been reported in several types of carcinomas. However, the expression of these aminopeptidases commonly demonstrates a negative correlation with both advanced and malignant carcinoma [19, 20, 21]. In contrast, P-LAP is positively correlated with both advanced stage and malignancy in this cancer.…”