Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia

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Abstract
BACKGROUND Local hypoxia may be one of the triggers of embryonic reawakening of the stroma and subsequent hyperplastic growth in the prostate. Using a cell culture model of human prostatic stromal cells, we investigated the effects of hypoxia on activation of hypoxia‐inducible factor 1 (HIF 1) and on the production of growth factors. METHODS Primary prostatic stromal cells were grown in normal and hypoxic (1% O2) atmosphere. Activation of HIF 1 was evaluated after different time intervals by Western blot. Induced secretion of growth factors VEGF, FGF‐7, TGF‐β, IL 8, and FGF‐2 were analyzed by ELISA. To confirm the in vitro findings we also performed immunohistochemistry of HIF 1α as well as pro‐collagen I, collagens I, III, and IV in the benign tissue of radical prostatectomy specimens. RESULTS HIF 1 is activated in a time‐dependent manner, already starting 1 hr after exposure of stromal cells to hypoxic conditions. Secretion of VEGF, FGF‐7, TGF‐β, FGF‐2, and IL 8 is increased under hypoxic in vitro conditions in comparison to normoxia. Levels of TGF‐β, VEGF, and IL 8 were rapidly and statistically significantly increased in the supernatant of hypoxic cells. Consistent with the in vitro findings, immunohistochemistry of HIF 1α in (benign prostatic hyperplasia) BPH tissue revealed strong HIF 1α nuclear staining in hyperplastic areas. No difference was observed in the collagen pattern between hyperplastic and normal prostate tissue. CONCLUSIONS Prostatic stromal cells respond to hypoxia by upregulation of secretion of several growth factors suggesting that hypoxia can trigger prostatic growth. Therefore, hypoxia might be a key factor contributing to the pathogenesis of BPH. Prostate 57: 57–65, 2003.