Approaches to understanding the importance and clinical implications of peroxisome proliferator-activated receptor gamma (PPARgamma) signaling in prostate cancer.

The development and maintenance of the prostate are dependent upon a complex series of interactions occurring between the epithelial and stromal tissues (Hayward and Cunha [2000]: Radiol. Clin. N. Am. 38:1-14). During the process of prostatic carcinogenesis, there are progressive changes in the interactions of the nascent tumor with its surrounding stroma and extracellular matrix. These include the development of a reactive stromal phenotype and the possible promotion, by stromal cells, of epithelial proliferation and loss of differentiated function (Hayward et al. [1996]: Ann. N. Y. Acad. Sci. 784:50-62; Grossfeld et al. [1998]: Endocr. Related Cancer 5:253-270; Rowley [1998]: Cancer Metastasis Rev. 17:411-419; Tuxhorn et al. [2002]: Clin. Cancer Res. 8:2912-2923). Many molecules play an as yet poorly defined role in establishing and maintaining a growth quiescent glandular structure in the adult. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a candidate regulator of prostatic epithelial differentiation and may play a role in restricting epithelial proliferation. PPARgamma agonists are relatively non-toxic and have been used with limited success to treat some prostate cancer patients. We would propose that a more complete understanding of PPARgamma biology, particularly in the context of appropriate stromal-epithelial and host-tumor interactions would allow for the selection of patients most likely to benefit from this line of therapy. In particular, it seems reasonable to suggest that the patients most likely to benefit may be those with relatively indolent low stage disease for whom this line of therapy could be a useful additive to watchful waiting.