IGF Axis Activity and Prostate Cancer Bone Metastasis

Howard University, Washington DC

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Abstract

DESCRIPTION (Provided by the applicant) Prostate cancers (CaP) metastasize to bone at a high frequency. While most bone cancers have a lytic effect to bone, a prostate epithelial cancer invasion of bone induces a blastic effect resulting in increased growth of both bone and CaP cells. Insulin-like growth factors (IGFs) have been found to be important regulators of bone and CaP cell growth. IGF activity in tissues is regulated by a complex group of interacting factors including several IGF-binding proteins (IGFBPs), IGFBP proteases, several matrix proteins and cell surface binding proteins. Collectively, these factors combine to up-regulate and down-regulate IGF activity in tissue specific ways. IGFBPs 3, 4 & 5 are especially important for regulation of IGF activity in bone cells and IGFBPs 3 and IGF activity may be essential for CaP cell growth. CaP cells can disrupt IGF axis activity by producing proteins which modify IGFBP concentration and, thus, their regulation of IGF activity. Prostate specific antigen (PSA) functions as an IGFBP protease. It degrades one of the IGFBPs involved in regulation of bone IGF activity. The objective of this study is to characterize the IGF axis response to CaP-bone cell co-culture. The specific aims of this research are (1) to determine if the accelerated growth of CaP cells in co-culture with normal bone cells is caused by IGFBP protease produced by CaP cells and (2) to establish an in vitro model for examination of the IGF-mediated CaP modulation of bone cell growth in order to evaluate those alterations in a bone cell environment more similar to that of bone in vivo. Primary cultures of normal bone cells will be co-cultured with cells from the CaP cell lines PC-3 and DU 145 in plastic dishes. The effect of co-culture on cell growth (of both cell types), IGF axis modulation of growth and apoptosis will be examined initially. Subsequently, a co-culture model of bone and bone-CaP cells embedded in a collagen matrix will be developed. Study results will be monitored using blotting (both Western immuno and ligand blots), radioimmuno-assay, microscopy, (electron and light) and molecular biology (immunohistochemistry, immunocytochemistry and in situ hybridization) techniques.