Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy
Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy
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DOI：
10.1016/s0002-9440(10)64286-1
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发表时间：
2003-05-01
影响因子：
6
通讯作者：
De Marzo, A
中科院分区：
文献类型：
--
作者：
van Leenders, GJLH;Gage, WR;De Marzo, A
在人前列腺上皮内，可以基于它们的角蛋白（K）表达来区分四种细胞群。基底细胞表达高水平的K5和K14以及p63，而它们具有非常低水平的雄激素受体、前列腺特异性抗原（PSA）、K8和K18。管腔分泌细胞缺乏p63、K5和K14，但表达高水平的K8、K18、雄激素受体和PSA。此外，已经鉴定出具有介于基底细胞和腔细胞之间的角蛋白表型的细胞，其共表达高水平的K5和K18（K5/18）以及肝细胞生长因子受体c-MET。虽然中间细胞已被认为是前列腺癌的前体细胞，但其生物学性质尚不明确。增殖性炎性萎缩（PIA）中的上皮细胞似乎是快速循环的，如Ki-67的表达所示，并且已经确定了PIA和高级别前列腺上皮内瘤变之间的形态学转变。PIA中的许多萎缩上皮管腔细胞是中间细胞的候选者，部分基于PSA和雄激素受体的弱表达、高水平的K8/18和缺乏p63。本研究的目的是进一步阐明PIA中拟议的中间细胞的表型，并定量确定这些中间细胞优先出现在PIA病变中的水平。使用K5、K14、K18和c-MET的抗体对中间细胞进行免疫化学证明。使用根治性前列腺切除术标本（n = 15）的中间细胞在正常分化的前列腺上皮和PIA的面积分数进行定量的网格点计数法。PIA病变的萎缩管腔细胞中有39.2 +/- 7.4%的细胞表达K5，而正常上皮中有2.4 +/- 2.3%的细胞表达K5（P < 0.00001）。相比之下，K14仅在3.0 +/- 3.2%的管腔细胞中表达。以前的研究表明，几乎100%的这些萎缩的管腔细胞是K8/18强阳性。c-MET存在于PIA中44.1 +/- 14.1%的管腔细胞中，但仅存在于正常上皮中2.1 +/- 2.8%的管腔细胞中（P < 0.00001）。为了明确地确定PIA中的中间腔细胞是否显示增殖活性增加和p27（kip 1）表达减少，进行Ki-67和K5以及p27（Kip 1）和K5的免疫荧光双染色。PIA的管腔细胞常同时表达K5和Ki-67。尽管p27（Kip 1）在正常上皮中K5阴性分化细胞中强烈表达，但在PIA腔室中的许多K5阳性细胞中不存在p27（Kip 1）染色。我们得出结论，细胞表型中间之间的基底和分泌细胞富集在PIA病变。PIA中大量高度增殖的中间细胞的发现提供了进一步的支持，这些细胞可能作为前列腺癌发生的优选靶细胞。
Within the human prostate epithelium four cell populations can be discriminated based on their expression of keratins (K). Basal cells express high levels of K5 and K14, as well as p63, whereas they have very low levels of androgen receptor, prostate-specific antigen (PSA), K8, and K18. Luminal secretory cells lack p63, K5, and K14 but express high levels of K8, K18, androgen receptor, and PSA. Additionally, cells have been identified with a keratin phenotype intermediate between basal and luminal cells that co-express high levels of K5 and K18 (K5/18) as well as hepatocyte growth factor receptor c-MET. Although intermediate cells have been proposed as precursor cells of prostate cancer, their biology is ill defined. Epithelial cells in proliferative inflammatory atrophy (PIA) appear to be cycling rapidly as indicated by expression of Ki-67, and morphological transitions have been identified between PIA and high-grade prostate intraepithelial neoplasia. Many of the atrophic epithelial luminal cells in PIA are candidates for intermediate cells based in part on weak expression of PSA and androgen receptor, high levels of K8/18, and lack of p63. The objective of this study was to further clarify the phenotype of the proposed intermediate cells in PIA and to quantitatively determine the level in which these intermediate cells preferentially occur in PIA lesions. Intermediate cells were immunohistochemically demonstrated using antibodies to K5, K14, K18, and c-MET. Using radical prostatectomy specimens (n = 15) the area fraction of intermediate cells in normally differentiated prostate epithelium and PIA were quantified by a grid point counting method. Atrophic luminal cells of PIA lesions expressed K5 in 39.2 +/- 7.4% of cells compared to 2.4 +/- 2.3% in normal epithelium (P < 0.00001). By contrast, K14 was only expressed in 3.0 +/- 3.2% of the luminal cells. Previous studies have shown that virtually 100% of these atrophic luminal cells are strongly positive for K8/18. c-MET was present in 44.1 +/- 14.1% of luminal cells in PIA but only in 2.1 +/- 2.8% of luminal cells in normal epithelium (P < 0.00001). To unambiguously determine whether intermediate luminal cells in PIA show increased proliferative activity and decreased p27(kip1) expression, double-staining immunofluorescence of Ki-67 and K5, as well as p27(Kip1) and K5 was performed. Luminal cells in PIA often co-expressed K5 and Ki-67. Although p27(Kip1) was strongly expressed in K5-negative differentiated cells in normal epithelium, p27(Kip1) staining was absent in many of the K5-positive cells in the luminal compartment of PIA. We conclude that cells phenotypically intermediate between basal and secretory cells are enriched in PIA lesions. The finding of a large number of highly proliferating intermediate cells in PIA provides further support that these cells may serve as preferred target cells in prostate carcinogenesis.