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.
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