Suzuki T, Kikkawa F, Ino K, Nagasaka T, Tamakoshi K, Mizutani S
Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Nagoya, Japan.
Oncology. 2001;60(3):258-67. doi: 10.1159/000055327.
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.
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.
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.
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.
中性内肽酶24.11（NEP）/CD10是一种细胞表面肽酶，可降解包括内皮素-1（ET-1）在内的多种生物活性肽。已知该酶在维持正常人类子宫内膜中ET-1调节的血管稳态中发挥作用。本研究的目的是调查NEP和ET-1在肿瘤性子宫内膜中的表达和定位，并阐明它们的表达与子宫内膜癌肿瘤分级的相关性。
对7例正常子宫内膜（绝经后）、5例非典型子宫内膜增生（AEH）和32例子宫内膜样腺癌的石蜡包埋组织切片进行NEP和ET-1表达的免疫组织化学分析。
在正常子宫内膜和AEH中，NEP免疫反应性在基质细胞中检测到，但在腺细胞中未检测到。相反，ET-1免疫反应性在腺细胞和基质细胞中均检测到。在1级子宫内膜腺癌的基质细胞中，NEP检测到高或中等量。然而，在2级和3级腺癌的基质细胞中观察到NEP免疫反应性显著降低。然而，除鳞状分化病变外，腺癌细胞中NEP未被免疫染色。ET-1免疫反应性在1级腺癌的基质细胞中弱检测到，但ET-1染色强度随肿瘤分级进展而增加。基质ET-1与基质NEP的染色评分比值与肿瘤分级呈正相关。
这些发现表明，随着肿瘤分级增加，子宫内膜腺癌基质细胞中NEP表达下调，而基质ET-1上调。本研究结果还表明，NEP可能通过降解某些肽生长因子如ET-1，在子宫内膜肿瘤的肿瘤转化、肿瘤进展和分化调节中发挥作用。
