PROSTATE STEM-CELL COMPARTMENTS - EXPRESSION OF THE CELL-CYCLE INHIBITOR P27(KIP1) IN, NORMAL, HYPERPLASTIC, AND NEOPLASTIC-CELLS

The stem cells of rapidly renewing tissues give rise to transiently pr oliferating cells, which in turn give rise to postmitotic terminally d ifferentiated cells. Although the existence of a transiently prolifera ting compartment has been proposed for the prostate, little molecular anatomical evidence for its presence has been obtained to date. We use d down-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) t o identify cells capable of entering the proliferative phase of the ce ll cycle and, therefore, competent to fulfill the role of the transien tly proliferating compartment, We examined the expression of p27(Kip1) in relation to its role in the development of prostatic carcinoma. Fo rmalin-fixed paraffin-embedded specimens from matched samples of norma l-appearing prostate tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia, primary adenocarcinomas, and pelv ic lymph node metastases were evaluated by comparative immunohistochem istry against p27Kip(1). In normal-appearing prostate epithelium, mode rate to strong nuclear staining of p27(Kip1) was present in greater th an 85% of the terminally differentiated secretory cells. The normal ba sal cell compartment, believed to contain prostatic stem cells, showed distinctive p27(Kip1) expression; acini in epithelial benign prostati c hyperplasia tissue contained more p27(Kip1)-negative basal cells tha n 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 p27(Kip1) negative, This intermediate layer was accentuated in the periurethral region, a s well as in prostate tissue that had been subjected to prior combined androgen blockade. We hypothesize that, on appropriate additional mit ogenic stimulation, cells in this layer, and other p27(Kip1)-negative basal cells, are competent for rapid entry into the cell cycle. Consis tent 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 p27(Kip1) as compared with th e surrounding normal-appearing secretory cells. In pelvic lymph node m etastases, p27(Kip1) expression was also reduced. In summary,our resul ts suggest that lack of nuclear p27(Kip1) protein may delineate a pote ntial transiently proliferating subcompartment within the basal cell c ompartment of the human prostate. In addition, these studies support t he hypothesis that reduced expression of p27(Kip1) removes a block to the cell cycle in human prostate epithelial cells and that dysregulati on of p27(Kip1) protein levels may be a critical early event in the de velopment of prostatic neoplasia.