Metastases from prostatic
adenocarcinoma (
prostate cancer) are characterized by their predilection for bone and typical osteoblastic features. An in vitro model of bone
metastases from
prostate cancer was developed using a bicompartment coculture system of mouse osteoblasts and human
prostate cancer 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 osteoblast proliferation. Moreover, these cells were able to induce osteoblast differentiation, as assessed by increased
alkaline phosphatase activity,
Osteocalcin expression, and calcified matrix formation. This osteoblastic reaction was confirmed in vivo by intrafemoral injection of MDA PCa 2b cells into
severe combined immunodeficiency disease mice. In contrast, the highly undifferentiated, bone-derived human
prostate cancer cell line PC3 did not produce 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. Moreover, 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 that primary mouse osteoblasts grown in the presence of MDA PCa 2b cells showed a shift in the pattern of gene expression with an increase in
mRNA-encoding
Procollagen type I and
Osteopontin and a decrease in
mRNA-encoding
proteins associated with myoblast differentiation, namely
myoglobin and
myosin light-chain 2. Taken together, these findings suggest that the bone-derived
prostate cancer cells MDA PCa 2a and MDA PCa 2b promote differentiation of osteoblast precursors to an osteoblastic phenotype through a Cbfa1-dependent 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 secreted by
prostate cancer cells that favor osteoblast differentiation. Moreover, it allows to screen for therapeutic agents blocking the osteoblast response to
prostate cancer.