Cellular senescence in the pathogenesis of benign prostatic hyperplasia

BACKGROUND. Senescent cells accumulate in tissues with age and show changes in protein expression that may influence the function of adjacent cells and contribute to the development of tissue pathologies associated with aging. Benign prostatic hyperplasia (BPH) is an extremely common disease of older men characterized by increased growth of prostatic epithelial and stromal cells. In BPH, there is an increased expression of II-1alpha by prostatic epithelial cells that results in elevated expression of FGF7 by stromal cells, which in turn is strongly correlated with epithelial proliferation. METHODS. Human BPH tissue and primary cultures of prostatic epithelial cells were analyzed by histochemical and quantitative assays for senescence-associated beta galactosidase (SA-beta gal). II-1alpha expression was localized by immunohistochemistry and II-1alpha tissue content determined by enzyme-linked immunoabsorption assay. RESULTS. Expression of II-1alpha is significantly increased in vitro when cultured prostatic epithelial cells undergo senescence. In BPH tissue a substantial population of epithelial cells express senescence-associated beta galactosidase (SA-beta gal), a marker of cellular senescence. By quantitative assay, SA-beta gal activity is correlated with both tissue levels of II-1alpha and the severity of BPH. CONCLUSIONS. One mechanism driving BPH in older men is the accumulation of senescent epithelial cells expressing II-1alpha, which in turn increases FGF7 secretion and proliferation of non-senescent epithelial cells. Thus there is a mechanistic linkage between cellular senescence and one of the most common pathologies of older men. (C) 2003 Wiley-Liss, Inc.