Blockade of Transforming Growth Factor-beta (TGFβ) Signaling Inhibits OsteoblasticTumorigenesis by a Novel Human Prostate Cancer Cell Line

BACKGROUND. The skeleton is the most common site of prostate cancer metastasis, which often results in osteoblastic lesions. The role of transforming growth factor-beta (TGF beta) signaling in prostate cancer-induced osteoblastic metastasis is not clear. We investigated the role of TGF beta signaling in prostate cancer-induced bone metastasis using a novel human prostate cancer cell line, PacMetUT1. METHODS. We injected PacMetUT1/Luc-GFP cells in male nude mice by intracardiac and intratibia injections and then investigated the effect of TGF beta signaling abrogation on osteoblastic tumor growth and incidence in vivo by using fluorescence and bioluminescence imaging analysis and quantifying bone and tumor volume by histomorphometry analysis. Osteoclasts were counted using TRAP assay. RESULTS. Osteoblastic bone metastasis in skull, rib, and femur was detected after 10-16 weeks of intracardiac injection of the PacMetUT1 cells. Stable knockdown of TGF beta 1 with an shRNA resulted in decreased tumor incidence and bone formation when the cells were directly injected into the tibiae. Systemic administration of either a small inhibitor of TGF beta type 1 receptor kinase or a pan TGF beta binding protein (BG(E)RII) also decreased bone tumor growth and osteoblastic bone formation in vivo after 7 weeks of treatment. CONCLUSIONS. Our results for the first time indicate that blockade of TGF beta signaling in the PacMetUT1 model significantly inhibits osteoblastic bone formation and tumor incidence. Thus, TGF beta signaling pathway may be a viable target for the prevention and treatment of prostate cancer-induced bone metastasis. Prostate 71: 1441-1454, 2011. (C) 2011 Wiley-Liss, Inc.