The Effects of Growth Factors Associated with Osteoblasts on Prostate Carcinoma Proliferation and Chemotaxis: Implications for the Development of Metastatic Disease*

The extensive mortality and morbidity associated with prostate cancer is caused by the high prevalence of metastatic disease at the time of diagnosis. The area most frequently involved in metastatic prostate cancer is the skeleton. Unlike other cancers, which metastasize to bone and destroy the bone matrix, prostate cancer is unique in that it is osteogenic, resulting in the formation of dense, sclerotic bone with high levels of osteoblastic activity. We proposed that factors produced by bone cells may be responsible for the development of prostate carcinoma metastasis. We studied the effects of these growth factors on prostate cell proliferation by 3Hthymidine incorporation and chemotaxis by the double-filter chamber method. Three prostate carcinoma cell lines were studied, LNCaP (androgen responsive) and PC-3 and DU-145 (androgen unresponsive). The bone-associated growth factors tested were: insulin-like growth factors I and II (IGF-I, IGF-II), transforming growth factor beta, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha), IGF-I and IGF-II significantly increased proliferation in all three cell lines, whereas IL-6, TNF-alpha, and IL-1 beta significantly decreased proliferation. Transforming growth factor beta induced a biphasic response in proliferation in DU-145 and PC-3 cells and produced no response on LNCaP cells. Increased cell chemotaxis occurred in the presence of IGF-I and IGF-II, and decreased cell chemotaxis occurred with the addition of TNF-alpha and IL-1 beta. These data indicate that growth factors produced by bone cells alter prostate carcinoma cell proliferation and chemotaxis and suggest that modulations of the production of these factors may be a potential therapeutic intervention in deterring the metastasis of prostate carcinoma to bone.