De Marzo A M, Meeker A K, Epstein J I, Coffey D S
Department of Pathology and The James Buchanan Brady Urological Institute, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287-2101, USA.
Am J Pathol. 1998 Sep;153(3):911-9. doi: 10.1016/S0002-9440(10)65632-5.
The stem cells of rapidly renewing tissues give rise to transiently proliferating cells, which in turn give rise to postmitotic terminally differentiated cells. Although the existence of a transiently proliferating compartment has been proposed for the prostate, little molecular anatomical evidence for its presence has been obtained to date. We used down-regulation of the cyclin-dependent kinase inhibitor p27Kip1 to identify cells capable of entering the proliferative phase of the cell cycle and, therefore, competent to fulfill the role of the transiently proliferating compartment. We examined the expression of p27Kip1 in relation to its role in the development of prostatic carcinoma. Formalin-fixed paraffin-embedded specimens from matched samples of normal-appearing prostate tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, primary adenocarcinomas, and pelvic lymph node metastases were evaluated by comparative immunohistochemistry against p27Kip1. In normal-appearing prostate epithelium, moderate to strong nuclear staining of p27Kip1 was present in greater than 85% of the terminally differentiated secretory cells. The normal basal cell compartment, believed to contain prostatic stem cells, showed distinctive p27Kip1 expression; acini in epithelial benign prostatic hyperplasia tissue contained more p27Kip1-negative basal cells than acini from non-benign prostatic hyperplasia tissue. A third layer of cells was identified that was sandwiched between the basal cells and the luminal cells, and this layer was consistently p27Kip1 negative. This intermediate layer was accentuated in the periurethral region, as well as in prostate tissue that had been subjected to prior combined androgen blockade. We hypothesize that, on appropriate additional mitogenic stimulation, cells in this layer, and other p27Kip1-negative basal cells, are competent for rapid entry into the cell cycle. Consistent with the fact that cancer cells are capable of cell division, all cases of high-grade prostatic intraepithelial neoplasia and invasive carcinoma also showed down-regulation of p27Kip1 as compared with the surrounding normal-appearing secretory cells. In pelvic lymph node metastases, p27Kip1 expression was also reduced. In summary, our results suggest that lack of nuclear p27Kip1 protein may delineate a potential transiently proliferating subcompartment within the basal cell compartment of the human prostate. In addition, these studies support the hypothesis that reduced expression of p27Kip1 removes a block to the cell cycle in human prostate epithelial cells and that dysregulation of p27Kip1 protein levels may be a critical early event in the development of prostatic neoplasia.
快速更新组织的干细胞会产生短暂增殖细胞，而短暂增殖细胞又会产生有丝分裂后终末分化细胞。尽管有人提出前列腺存在短暂增殖区室，但迄今为止，几乎没有获得其存在的分子解剖学证据。我们通过下调细胞周期蛋白依赖性激酶抑制剂p27Kip1来识别能够进入细胞周期增殖期的细胞，因此能够充当短暂增殖区室的角色。我们研究了p27Kip1的表达及其在前列腺癌发生发展中的作用。通过针对p27Kip1的比较免疫组织化学方法，对外观正常的前列腺组织、良性前列腺增生、高级别前列腺上皮内瘤变、原发性腺癌和盆腔淋巴结转移的匹配样本的福尔马林固定石蜡包埋标本进行了评估。在外观正常的前列腺上皮中，超过85%的终末分化分泌细胞呈现中度至强的p27Kip1核染色。被认为含有前列腺干细胞的正常基底细胞区室显示出独特的p27Kip1表达；上皮性良性前列腺增生组织中的腺泡比非良性前列腺增生组织中的腺泡含有更多p27Kip1阴性的基底细胞。识别出了夹在基底细胞和管腔细胞之间的第三层细胞，这一层始终为p27Kip1阴性。这一中间层在尿道周围区域以及先前接受过联合雄激素阻断的前列腺组织中更为明显。我们推测，在适当的额外促有丝分裂刺激下，这一层中的细胞以及其他p27Kip1阴性的基底细胞能够迅速进入细胞周期。与癌细胞能够进行细胞分裂这一事实一致，与周围外观正常的分泌细胞相比，所有高级别前列腺上皮内瘤变和浸润性癌病例也显示出p27Kip1的下调。在盆腔淋巴结转移中，p27Kip1表达也降低。总之，我们的结果表明，缺乏核p27Kip1蛋白可能界定了人类前列腺基底细胞区室内一个潜在的短暂增殖亚区室。此外，这些研究支持这样的假说，即p27Kip1表达降低消除了人类前列腺上皮细胞中细胞周期的阻滞，并且p27Kip1蛋白水平的失调可能是前列腺肿瘤发生发展中的一个关键早期事件。
