Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway

Metastases from prostatic adenocarcinoma (prostate cancer) are characterize d by their predilection for bone and typical osteoblastic features. An in v itro model of bone metastases from prostate cancer was developed using a bi compartment coculture system of mouse osteoblasts and human prostate canter cells. In this model, the bone-derived prostate cancer cell lines MDA PCa 2a and MDA PCa 2b induced a specific and reproducible increase in osteoblas t proliferation, Moreover, these cells were able to induce osteoblast diffe rentiation, as assessed by increased alkaline phosphatase activity, Osteoca lcin expression, and calcified matrix formation. This osteoblastic reaction was confirmed in vivo by intrafemoral injection of MDA PCa 2b cells into s evere combined immunodeficiency disease mice. In contrast, the highly undif ferentiated, bone-derived human prostate cancer cell line PC3 did not produ ce an osteoblastic reaction in vitro and induced osteolytic lesions in vivo . The osteoblast differentiation induced by MDA PCa 2b cells was associated with up-regulation of the osteoblast-specific transcriptor factor Cbfa1. M oreover, treatment of osteoblasts with conditioned medium obtained from MDA PCa 2b cells resulted in up-regulation of Cbfa1 and Osteocalcin expression . In support of the differentiation studies. a microarray analysis showed t hat primary mouse osteoblasts grown in the presence of MDA PCa 2b cells sho wed a shift in the pattern of gene expression with an increase in mRNA-encr oding Procollagen type I and Osteopontin and a decrease in mRNA-encoding pr oteins associated with myoblast differentiation, namely myoglobin and myosi n light-chain 2. Taken together, these findings suggest that the bone-deriv ed prostate cancer cells MDA PCa Za and MDA PCa 2b promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-depen dent pathway. These results also established that soluble factors produced by prostate cancer cells can induce expression of osteoblast-specific genes . This in vitro model provides a valuable system to isolate molecules secre ted by prostate cancer cells that favor osteoblast differentiation. Moreove r. it allows to screen for therapeutic agents blocking the osteoblast respo nse to prostate cancer.