We propose to investigate the pathophysiological role and the potential diagnostic importance of the insulin-like growth factors (IGFs), their receptors, and their binding proteins (IGFBPs) in the etiology and pathogenesis of benign prostatic hyperplasia (BPH). BPH is the most common proliferative disorder affecting men, and is a major cause of morbidity and health care expenditure in older men. At this time, however, there are no reliable biochemical markers of this disease available to clinicians caring for older men. The pathophysiology of BPH is not yet elucidated, but appear to be related to interactions between the stromal and epithelial components of the prostate and to involve locally produced growth factors. The IGFs are important mitogenic factors that have been shown to have autocrine-paracrine, as well as endocrine roles in normal and malignant cellular growth. The IGFs exert their actions by binding to specific cell surface receptors (IGF-R) which mediate cellular proliferation, and also bind to a family of specific IGFBPs which modulate IGF action on cells. Using primary human prostatic cell culture systems, we have established the presence of a fully functioning IGF axis within the prostate. This system includes IGF-II production by prostate stromal cells (PC-S), IGF binding to IGF-R and IGF action on prostate epithelial cells (PC-E), as well as IGFBP production and proteolysis. Thus, the human prostate comprises an autocrine-paracrine system of IGF interaction. Additionally, we have already identified several IGF related abnormalities in PC-S from BPH patients. These include a ten fold increase in the levels of expression of IGF-II mRNA, a four fold increase in the levels of expression of the IGF-R mRNA and a dramatic fall in the levels of the mRNA and peptide levels of IGFBP-2 coupled with an appearance of IGFBP-5 peptide and mRNA not seen in normal PC-S. These findings suggest that the PC-S in BPH patients harbors molecular abnormalities involving the IGF axis. These abnormalities may promote abnormal cellular proliferation via the IGF system. We plan to further characterize the IGF system in cultured prostate cells and in prostate tissue from BPH patients and from normal controls, in order to verify our preliminary findings, and to try to pinpoint the primary IGF-related molecular abnormality associated with BPH. Using specific methodologies for the identification of IGF related molecules, we will attempt to identify corresponding IGF and IGFBP markers in the sera and seminal plasma of men with BPH. We expect to observe specific elevations of PC-S-derived IGF-H and IGFBP-5 in the serum and/or seminal plasma of patients with BPH relative to age matched controls. The identification of specific, IGF-related abnormalities in cultured cells, tissues, and bodily fluids from BPH patients could have major diagnostic significance and may lead the way for earlier and more directed therapy for this common disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK047591-01
Application #
3248810
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1993-09-30
Project End
1996-08-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Shim, Melanie L; Levitt Katz, Lorraine E; Davis, Jason et al. (2004) Insulin-like growth factor binding protein-3 is a novel mediator of apoptosis in insulin-secreting cells. Growth Horm IGF Res 14:216-25
Wetterau, Lawrence A; Francis, Malik J; Ma, Liqun et al. (2003) Insulin-like growth factor I stimulates telomerase activity in prostate cancer cells. J Clin Endocrinol Metab 88:3354-9
Moore, Michael G; Wetterau, Lawrence A; Francis, Malik J et al. (2003) Novel stimulatory role for insulin-like growth factor binding protein-2 in prostate cancer cells. Int J Cancer 105:14-9
Liu, Bingrong; Weinzimer, Stuart A; Gibson, Tara Beers et al. (2003) Type Ialpha collagen is an IGFBP-3 binding protein. Growth Horm IGF Res 13:89-97
Franklin, Sherry Lynn; Ferry Jr, Robert J; Cohen, Pinchas (2003) Rapid insulin-like growth factor (IGF)-independent effects of IGF binding protein-3 on endothelial cell survival. J Clin Endocrinol Metab 88:900-7
Ngo, Tung H; Barnard, R James; Cohen, Pinchas et al. (2003) Effect of isocaloric low-fat diet on human LAPC-4 prostate cancer xenografts in severe combined immunodeficient mice and the insulin-like growth factor axis. Clin Cancer Res 9:2734-43
Ngo, Tung H; Barnard, R James; Leung, Pak-Shan et al. (2003) Insulin-like growth factor I (IGF-I) and IGF binding protein-1 modulate prostate cancer cell growth and apoptosis: possible mediators for the effects of diet and exercise on cancer cell survival. Endocrinology 144:2319-24
Grimberg, Adda; Liu, Bingrong; Bannerman, Peter et al. (2002) IGFBP-3 mediates p53-induced apoptosis during serum starvation. Int J Oncol 21:327-35
Ngo, Tung H; Barnard, R James; Tymchuk, Christopher N et al. (2002) Effect of diet and exercise on serum insulin, IGF-I, and IGFBP-1 levels and growth of LNCaP cells in vitro (United States). Cancer Causes Control 13:929-35
Monzavi, Roshanak; Cohen, Pinchas (2002) IGFs and IGFBPs: role in health and disease. Best Pract Res Clin Endocrinol Metab 16:433-47

Showing the most recent 10 out of 35 publications