Benign prostatic hyperplasia (BPH) is the most common neoplastic disease in men. One in every four men in the United States will require surgery to relieve symptoms of urinary-outlet obstruction due to BPH. This makes BPH the second leading cause of surgery in men and results in an overall medical cost that exceeds one billion dollars annually in the U.S. Despite these alarming statistics the etiology of BPH is poorly understood. Consequently, the only approaches to treatment are aimed at reducing the symptoms of BPH. This competing renewal application proposes experiments to test the hypothesis that prostatic growth is controlled by members of the heparin-binding growth factor (HBGF) and transforming growth factor Beta (TGF-Beta) families of growth modulators. The approach will be 1) to ascertain whether members of these families of growth modulators are expressed in human prostate and if their expression is altered in BPH, and (2) to utilize cultured prostatic stromal and epithelial cells derived from normal and BPH prostates to investigate the interaction of growth modulators in regulating prostatic cell growth.
Specific aim I proposes five objectives that will determine if growth of the prostatic stroma is regulated by the HBGF, basic fibroblast growth factor (beta FGF) and TGF-Beta and whether the expression of these factors and their receptors is altered in BPH.
Specific aim II proposes three objectives to determine if the HBGF member, keratinocyte growth factor (KGF), acts as a paracrine effector to regulate growth of the prostatic epithelium and whether KGF expression and receptor protein is altered in BPH. Prior studies have 1) identified betaFGF as a positive stimulator of stromal cell proliferation, 2) KGF as a positive stimulator of epithelial cell proliferation, and 3) TGF-Beta as a negative effector of both stromal and epithelial cell proliferation. We propose that in normal adult prostate (steady-state growth) the influence of betaFGF is equal to the influence of TGF-Beta on the stroma and the influence of KGF is equal to the influence of the TGF-Beta on the epithelium. In BPH (unbalanced growth) the influence of betaFGF > TGF-Beta on the stroma and the influence of KGF > TGF-Beta on the epithelium. If imbalances in growth modulators can be shown to accompany BPH, it may be possible to design agents for the medical management of BPH that are directed at the pathophysiology of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031063-13
Application #
2138562
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1982-01-01
Project End
1996-06-30
Budget Start
1994-07-01
Budget End
1996-06-30
Support Year
13
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Surgery
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Story, M T; Hopp, K A; Molter, M (1996) Expression of transforming growth factor beta 1 (TGF beta 1), -beta 2, and- beta 3 by cultured human prostate cells. J Cell Physiol 169:97-107
Begun, F P; Story, M T; Hopp, K A et al. (1995) Regional concentration of basic fibroblast growth factor in normal and benign hyperplastic human prostates. J Urol 153:839-43
Story, M T (1995) Regulation of prostate growth by fibroblast growth factors. World J Urol 13:297-305
Story, M T; Hopp, K A; Molter, M et al. (1994) Characteristics of FGF-receptors expressed by stromal and epithelial cells cultured from normal and hyperplastic prostates. Growth Factors 10:269-80
Story, M T; Hopp, K A; Meier, D A et al. (1993) Influence of transforming growth factor beta 1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate-derived fibroblasts. Prostate 22:183-97
Story, M T (1991) Polypeptide modulators of prostatic growth and development. Cancer Surv 11:123-46
Story, M T; Livingston, B; Baeten, L et al. (1989) Cultured human prostate-derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 15:355-65
Story, M T (1989) Cultured human foreskin fibroblasts produce a factor that stimulates their growth with properties similar to basic fibroblast growth factor. In Vitro Cell Dev Biol 25:402-8