The etiology of prostate cancer is essentially not understood. Molecular mechanisms responsible for initiation and progression remain largely unknown, and the endogenous or systemic factors involved in mediating rapid and metastatic growth are generally unidentified. It is clear, however, that major determinants of the malignant phenotype depend on various growth-stimulatory and inhibitory factors and their receptors whose inappropriate expression or loss disrupt normal regulation of cell proliferation and differentiation. Tissue culture is perhaps our most versatile tool for studying the expression and interaction of growth factors in living cells. We hypothesize that the continued development of optimal cell culture techniques and in-depth study of human prostate cell cultures derived from normal and malignant tissues will lead to the recognition of factors involved in the biologic progression of the malignant phenotype. Using the established and efficient retrieval, culture and analysis techniques that we have refined during the past ten years, we propose to maintain and expand our characterization of the response to and expression of growth factors by monolayer cultures of prostatic epithelial cells derived from normal tissues and moderate-grade cancers. We further propose to increase the diversity of malignant tissue examined by expanding our studies to cell cultures derived from high-grade cancers, which will be accessed by ultrasound-guided needle biopsies. The phenotype of these cells will be compared to that of cells obtained from normal tissues and moderate-grade cancers. In addition, we plan to optimize conditions for 3-dimensional growth of prostate cells. We project that the phenotype and response to and expression of growth factors of cells in 3-dimensional culture will differ from that in monolayer culture, and will be more reflective of the in vivo situation. Our previous studies have shown important regulatory roles for epidermal growth factor, fibroblast growth factors, insulin-like growth factors, prostate specific antigen, transforming growth factor-B, vitamin A, and vitamin D. Our future efforts will emphasize study of the interactions of these factors and their receptors in monolayer and 3-dimensional cultures of normal and malignant cell populations at the molecular and cellular levels. Our ultimate goal is an inclusive definition of the autocrine, paracrine and endocrine pathways of growth regulation in the human prostate and recognition of deregulation in prostate cancer. Our multifaceted approach should provide information which will facilitate the logical design of new preventative, diagnostic, and therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK047551-01
Application #
3248768
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
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Peehl, D M; Sellers, R G (1997) Induction of smooth muscle cell phenotype in cultured human prostatic stromal cells. Exp Cell Res 232:208-15
Peehl, D M; Edgar, M G; Cramer, S D et al. (1997) Parathyroid hormone-related protein is not an autocrine growth factor for normal prostatic epithelial cells. Prostate 31:47-52
Nunn, S E; Peehl, D M; Cohen, P (1997) Acid-activated insulin-like growth factor binding protein protease activity of cathepsin D in normal and malignant prostatic epithelial cells and seminal plasma. J Cell Physiol 171:196-204
Dong, G; Rajah, R; Vu, T et al. (1997) Decreased expression of Wilms' tumor gene WT-1 and elevated expression of insulin growth factor-II (IGF-II) and type 1 IGF receptor genes in prostatic stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol Metab 82:2198-203
Peehl, D M; Sellers, R G; McNeal, J E (1996) Keratin 19 in the adult human prostate: tissue and cell culture studies. Cell Tissue Res 285:171-6
Peehl, D M; Cohen, P; Rosenfeld, R G (1996) The role of insulin-like growth factors in prostate biology. J Androl 17:2-4
Cramer, S D; Peehl, D M; Edgar, M G et al. (1996) Parathyroid hormone--related protein (PTHrP) is an epidermal growth factor-regulated secretory product of human prostatic epithelial cells. Prostate 29:20-9
Cramer, S D; Chen, Z; Peehl, D M (1996) Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol 156:526-31
Peehl, D M; Wong, S T; Rubin, J S (1996) KGF and EGF differentially regulate the phenotype of prostatic epithelial cells. Growth Regul 6:22-31
Girinsky, T; Koumenis, C; Graeber, T G et al. (1995) Attenuated response of p53 and p21 in primary cultures of human prostatic epithelial cells exposed to DNA-damaging agents. Cancer Res 55:3726-31

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