Preprostatectomy: A clinical model to study stromal-epithelial interactions

The preprostatectomy setting serves as a valuable clinical model for early developmental clinical trials for evaluating promising agents for chemoprevention. In the preprostatectomy model, study agents are administered between the diagnostic biopsy for prostate cancer and definitive therapy. The prostatic tissue that is available after prostatectomy allows for biomarker evaluation of all the components of the prostate, including the glandular epithelium, blood vessels, and the stroma. This provides an opportunity to study the reciprocal interactions between the stroma and the epithelium. Morphologic studies suggest that prostatic stromal cells play a critical role in affecting the growth and maturation of prostatic epithelium. Experimental studies in tissue culture show that carcinoma-associated stromal cells can promote prostatic carcinogenesis, and normal stromal cells may be able to inhibit prostatic carcinogenesis by inducing differentiation and decreasing the proliferation of the epithelium. Although the complex molecular mechanisms through which stroma modulates the epithelial cell phenotype remain to be elucidated, there are several well-characterized signaling pathways, such as for growth factors and steroid hormones, that are likely to contribute to the modulation of transformed epithelial cells. There is evidence of an association between increased serum levels of IGF-I and an increased risk of prostate cancer. The IGF system appears to play an important role in the development of prostate cancer by modulation of paracrine pathways, and also by modulation of the concentrations of different stromal and epithelial IGFBP, which are differentially expressed in the epithelium and stroma. Nerve growth factor is capable of stimulating a proliferative response via a high affinity Trk receptor present in normal and malignant prostate epithelia, and alternatively can mediate apoptosis via the low affinity p75NTR receptor that is progressively lost from the malignant prostate. As the role of each stromal element involved in carcinogenesis becomes further defined, these elements offer promising targets for new chemopreventive strategies.