Dihydrotestosterone and Testosterone, but not DHEA or Estradiol, Differentially Modulate IGF-I, IGFBP - 2 and IGFBP-3 Gene and Protein Expression in Primary Cultures of Human Prostatic Stromal Cells

Prostate cancer is one of the four most common cancers in the U.S., affecting one of six men. Increased serum levels of androgens and IGF-I are associated with an augmented risk of prostate cancer. Dihydrotestosterone (DHT) and testosterone (T) stimulate prostate cancer cell growth, development, and function, whereas the effects of DHT and T in prostate stromal cells, and of DHEA in prostate cancer or stromal cells, are uncertain. We investigated the actions of DHT, T, DHEA, and E 2 on IGF-I, IGF-II, IGF-IR, IGFBP-2, IGFBP-3 and IGFBP-5 in primary cultures of human prostatic stromal cells by assessing cell proliferation, mRNA expression, and protein secretion by MTT growth assay, quantitative real time PCR, and ELISA, respectively. DHT and T each increased IGF-I (7-fold) and decreased IGFBP-3 (2-fold) mRNA expression and protein secretion in a dose and time dependent manner, and increased IGFBP-2 (2-fold) mRNA in a dose and time dependent manner. DHEA and E 2 did not significantly alter these measures. Flutamide abolished the DHT-modulated increases in IGF-I and IGFBP-2, suggesting that the influences of DHT and T on these measures were androgen receptor mediated. None of the four steroids significantly affected IGF-I receptor, IGF-II or IGFBP-5 mRNA levels or stromal cell proliferation. The effects of DHT on IGF-I, IGFBP-2 and IGFBP-3 were more pronounced in stromal cultures that did not express desmin. These data suggest that DHT and T promote prostate growth partly via modulation of the stromal cell IGF axis, with potential paracrine effects on prostate epithelial cells.