Abstract
Metastatic prostate tumors in the bone microenvironment stimulate bone resorption, resulting in release of growth factors from the bone matrix that play important roles in tumor growth and osteoclast induction. Transforming growth factor beta (TGFbeta) is one of the most abundantly stored cytokines in bone matrix, regulating diverse biological activities. Here we evaluate its involvement in prostate tumor growth in the bone microenvironment, comparing with tumor growth in the subcutaneous microenvironment as a control. Rat prostate tumors were transplanted onto the cranial bone and into the subcutis of F344 male rats. Tumor cell proliferation, apoptosis, and TGFbeta signal transduction were compared between the tumor-bone interface and the tumor-subcutaneous interface. Effects of TGFbeta on osteoclast differentiation were also evaluated in vitro. Inhibitory effects of TGFbeta receptor 1 antisense oligonucleotide on TGFbeta signaling, osteolysis, osteoblasts, and tumor growth were examined in vivo. Osteolytic changes were extensively observed at the tumor-bone interface, where the TGFbeta level, TGFbeta signal transduction, and tumor cell proliferation were higher than at the tumor-subcutaneous interface. In vitro treatment with receptor activator of nuclear factor-kappaB ligand induced osteoclast differentiation of bone marrow stromal cells, and additional exposure to TGFbeta exerted promotive effects on osteoclast induction. Intratumoral injection of TGFbeta receptor 1 antisense oligonucleotide significantly reduced TGFbeta signal transduction, osteolysis, induction of osteoclast and osteoblast, and tumor cell proliferation. Thus, we experimentally show that TGFbeta derived from bone matrix promotes cell proliferation of rat prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment.