Clinical prostate cancer (PCa) is dominated by complications arising from bone metastases. Bone metastases from PCa are characteristically blastic, suggesting an interaction between PCa cells and cells from the osteoblastic lineage. Using an in vitro model of bone metastases, we showed that PCa cells induce osteoblast growth and differentiation and upregulated the osteoblast-specific transcription factor Cbfal and its target genes collagen type I and osteocalcin. Cbfal activity is controlled by mitogen-activated protein kinases (MAPKs). Insulin-like growth factors (IGFs) play key roles in bone formation and are important regulators of the activity of mature osteoblasts. IGFs exert their action through the type 1 IGF receptor (IGF1R). Activation of the ras/MAPK pathway through Shc, an immediate substrate of IGF1R, favors differentiation in several cell types. PCa cells can regulate the bioavailable levels of IGFs, which have been implicated in the pathogenesis of osteoblastic bone metastases of PCa. We hypothesize that PCa cells increase the levels of bioavailable IGFs in the bone microenvironment, which activates the MAPK cascade, which subsequently activates Cbfal, leading to osteoblast differentiation and/or increased production of extracellular matrix (ECM) proteins. The increased levels of bioavailable IGFs and/or ECM proteins in the bone microenvironment then increase PCa cell growth and/or survival. If we prove our hypothesis, we will have identified a critical event in PCa progression, and this finding may lead to the design and development of novel therapies.
Our Specific Aims are (1) To assess whether IGF1R is involved in osteoblast differentiation through a Cbfa1-dependent pathway. We will use the Cre/LoxP system, mouse lines expressing the IoxP-modified Igf1r gene, and osteoblast-specific expression of the Cre transgene. (2) To study the involvement of Igf1r signaling in the induction of osteoblast differentiation in our in vitro model system by using wild-type mice and cre/IoxP-Igf1r transgenic mice. (3) To study the role of the IGF-I and Cbfal signaling pathways in the growth and survival of PCa cells in our in vivo (immunodeficient cre/IoxP-Igf1r transgenic mice) and in vitro model systems.
