INSULIN-LIKE GROWTH-FACTOR AXIS ABNORMALITIES IN PROSTATIC STROMAL CELLS FROM PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA

Benign prostatic hyperplasia (BPH) is a common proliferative disorder of unknown etiology. To assess whether patients with BPH have alterations in their prostatic IGF axis, we measured the expression (by Northern blotting) and the production (by Western ligand blotting and RIA) of insulin-like growth factor-II (IGF-II) and IGF-binding proteins (IGFBPs) in prostatic epithelial and stromal cell strains grown from normal (n = 7), hyperplastic (n = 7), and malignant (n = 5) surgical specimens. Levels of IGF-II messenger ribonucleic acid (mRNA; normalized for actin expression) were 10-fold higher in BPH stromal cell strains compared to those in normal stromal cell strains (P < 0.0001). Western ligand blotting of conditioned medium (CM) from normal stromal cells demonstrated the presence of IGFBP-2, -3, and -4. In the CM of BPH stromal cells, IGFBP-2 levels were dramatically reduced to less than 20% of normal (P < 0.001). Additionally, IGFBP-5, which was not observed in significant amounts in normal stromal cell-CM, was found in large quantities in BPH stromal cell-CM. Northern blot analysis of mRNA from normal and BPH stromal cells demonstrated a 5-fold decrease in IGFBP-2 mRNA (P < 0.001) and a 4-fold increase in IGFBP-5 mRNA (P < 0.01) in BPH compared to normal cells. In prostate stromal cells from cancer specimens, no abnormalities were found. No abnormalities were observed in the IGF axis parameters evaluated in prostate epithelial cells from BPH or cancer strains. We conclude that prostatic stromal cell strains isolated from patients with BPH hyperexpress the mRNA for IGF-II and IGFBP-5 while expressing reduced amounts of IGFBP-2 mRNA. IGFBP, but not IGF-II, peptide levels in CM correspond to the mRNA differences. This is the first documentation of altered gene and protein expression in this common disease. We speculate that these abnormalities in the IGF axis may be important in the pathogenesis of BPH.