Understanding the cellular and molecular changes in the bone microenvironment is important for developing novel therapeutics to control breast cancer bone metastasis. Although the underlying mechanism(s) of bone metastasis has been the focus of intense investigation, relatively little is known about complex molecular interactions between malignant cells and bone stroma. Using a murine syngeneic model that mimics osteolytic changes associated with human breast cancer, we examined the role of tumor-bone interaction in tumor-induced osteolysis and malignant growth in the bone microenvironment. We identified transforming growth factor-beta receptor 1 (TGF-betaRI) as a commonly upregulated gene at the tumor-bone (TB) interface. Moreover, TGF-betaRI expression and activation, analyzed by nuclear localization of phospho-Smad2, was higher in tumor cells and osteoclasts at the TB interface as compared to the tumor-alone area. Furthermore, attenuation of TGF-beta activity by neutralizing antibody to TGF-beta or TGF-betaRI kinase inhibitor reduced mammary tumor-induced osteolysis, TGF-betaRI expression and its activation. In addition, we demonstrate a potential role of TGF-beta as an important modifier of receptor activator of NF-kappaB ligand (RANKL)-dependent osteoclast activation and osteolysis. Together, these studies demonstrate that inhibition of TGF-betaRI signaling at the TB interface will be a therapeutic target in the treatment of breast cancer-induced osteolysis.

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 β β β (TGFβ β β β) 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 β β β signal transduction were compared between the tumor-bone interface and the tumorsubcutaneous interface. Effects of TGFβ β β β on osteoclast differentiation were also evaluated in vitro. Inhibitory effects of TGFβ β β β receptor 1 antisense oligonucleotide on TGFβ β β β signaling, osteolysis, osteoblasts, and tumor growth were examined in vivo. Osteolytic changes were extensively observed at the tumor-bone interface, where the TGFβ β β β level, TGFβ β β β signal transduction, and tumor cell proliferation were higher than at the tumor-subcutaneous interface. In vitro treatment with receptor activator of nuclear factor-κ κ κ κB ligand induced osteoclast differentiation of bone marrow stromal cells, and additional exposure to TGFβ β β β exerted promotive effects on osteoclast induction. Intratumoral injection of TGFβ β β β receptor 1 antisense oligonucleotide significantly reduced TGFβ β β β signal transduction, osteolysis, induction of osteoclast and osteoblast, and tumor cell proliferation. Thus, we experimentally show that TGFβ β β β 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) B one metastases are the most critical complications with advanced prostate cancer, resulting in severe pain, morbidity, and often mortality.(1,2) Conventional therapies do not allow a curative outcome for prostate cancer bone metastasis, (3,4) and elucidation of molecular mechanisms that regulate prostate tumor growth in the bone microenvironment is essential for development of new therapeutic approaches to prevent bone metastasis.Once cancer cells reach the bone microenvironment, a reciprocal cellular interaction between tumor and bone stromal cells was observed. (5,6) This interaction between the tumor and bone stromal cells has been commonly referred to as a "vicious cycle", whereby tumor and stromal cells in the bone secrete several factors beneficial to each other. (7)(8)(9) In the vicious cycle, metastatic prostate tumor cells in the bone microenvironment produce cytokines that stimulate osteoclastic bone resorption.This then results in the release of growth factors such as TGFβ, (10) insulin-like growth factors, (10) and bone morphological proteins (11) from the bone matrix. In bone metastatic sites, prostate tumor cells, o...

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