ldn-193189 and Bone-Neoplasms

Induction of new bone formation is frequently seen in the bone lesions from prostate cancer. However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, 2 xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from prostate cancer bone metastases. When implanted subcutaneously in severe combined immunodeficient (SCID) mice, MDA-PCa-118b induced strong ectopic bone formation while MDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (secretome) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of bone morphogenetic protein BMP4 and several cytokines including interleukin-8, growth-related protein (GRO), and CCL2. We showed that BMP4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA-PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treatment with BMP4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCID mice bearing MDA-PCa-118b tumors with LDN-193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone.

Topics: Adenocarcinoma; Animals; Autocrine Communication; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type I; Bone Neoplasms; Cell Line, Tumor; Culture Media, Conditioned; Cytokines; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, SCID; Neoplasm Proteins; Ossification, Heterotopic; Osteoblasts; Osteogenesis; Prostatic Neoplasms; Pyrazoles; Pyrimidines; Recombinant Proteins; Subcutaneous Tissue; Xenograft Model Antitumor Assays