Increased growth factor production in a human prostatic stromal cell culture model caused by hypoxia.
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% O(2)) atmosphere. Activation of HIF 1 was evaluated after different time intervals by Western blot. Induced secretion of growth factors VEGF, FGF-7, TGF-beta, IL 8, and FGF-2 were analyzed by ELISA. To confirm the in vitro findings we also performed immunohistochemistry of HIF 1alpha 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-beta, FGF-2, and IL 8 is increased under hypoxic in vitro conditions in comparison to normoxia. Levels of TGF-beta, 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 1alpha in (benign prostatic hyperplasia) BPH tissue revealed strong HIF 1alpha 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.
Berger
Andreas P
AP
Department of Urology, University of Innsbruck, Austria. andreas.p.berger@uibk.ac.at
Kofler
Kurt
K
Bektic
Jasmin
J
Rogatsch
Hermann
H
Steiner
Hannes
H
Bartsch
Georg
G
Klocker
Helmut
H
D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000378:metabolism; D019382:Human Growth Hormone / Q000096:biosynthesis*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D011467:Prostate / Q000166:cytology / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D024042:Collagen Type I; D024061:Collagen Type III; D024141:Collagen Type IV; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C496453:FGF7 protein, human; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008222:Lymphokines; D009687:Nuclear Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D019382:Human Growth Hormone; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors