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.