Transforming growth factor β derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation‐associated osteolysis in the bone microenvironment

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 β (TGFβ) 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 TGFβ signal transduction were compared between the tumor–bone interface and the tumor–subcutaneous interface. Effects of TGFβ on osteoclast differentiation were also evaluated in vitro . Inhibitory effects of TGFβ receptor 1 antisense oligonucleotide on TGFβ signaling, osteolysis, osteoblasts, and tumor growth were examined in vivo . Osteolytic changes were extensively observed at the tumor–bone interface, where the TGFβ level, TGFβ signal transduction, and tumor cell proliferation were higher than at the tumor–subcutaneous interface. In vitro treatment with receptor activator of nuclear factor‐κB ligand induced osteoclast differentiation of bone marrow stromal cells, and additional exposure to TGFβ exerted promotive effects on osteoclast induction. Intratumoral injection of TGFβ receptor 1 antisense oligonucleotide significantly reduced TGFβ signal transduction, osteolysis, induction of osteoclast and osteoblast, and tumor cell proliferation. Thus, we experimentally show that TGFβ derived from bone matrix promotes cell proliferation of rat prostate cancer and osteoclast activation‐associated osteolysis in the bone microenvironment. ( Cancer Sci 2008; 99: 316–323)