DEVELOPMENT OF HUMAN PROSTATE-CANCER MODELS FOR CHEMOPREVENTION AND EXPERIMENTAL THERAPEUTICS STUDIES

The progression of human prostate cancer from histomorphologic to clin ical expression often requires several decades. This study emphasizes the importance of developing relevant human prostate cancer models to study the molecular events leading to prostate cancer progression. The se models will provide a rational basis for chemopreventive and treatm ent strategies to retard the progression of human prostate cancer from its localized to its metastatic state. In our laboratory, we have est ablished the LNCaP progression and ARCaP models and the in vitro three -dimensional growth models involving prostate cancer and bone stroma t o study the progression of prostate cancer. We propose that prostate c ancer may progress from an androgen-dependent to an androgen-independe nt stale. While existing as androgen-independent tumors (defined as tu mors capable of growing in castrated hosts and secreting PSA in serum) , prostate cancer may assume three different phenotypes as it progress es: androgen-independent while remaining androgen-responsive; androgen -independent and unresponsive to androgen stimulation; and androgen-in dependent but suppressed by androgen. It is conceivable that any andro gen-independent human prostate cancer may contain variable proportions of cells that exhibit these three phenotypes. This concept may have i mportant implications in determining strategies for chemopreventive an d therapeutic trials. We have established three-dimensional growth mod els of prostate cancer cells either in collagen gel or microgravity-si mulated growth conditions to form viable and functional organoids whic h contain prostate cancer epithelial cells admired with prostate or bo ne stromal cells. These in vitro models combined with the in vivo mode ls described above will enhance our understanding of the regulatory me chanism of prostate cancer growth and progression, and hence could imp rove efficiency in screening chemopreventive and therapeutic agents wh ich alter the biologic behaviors of human prostate cancer. (C) 1998 Wi ley-Liss, Inc.