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

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 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...

Targeting Bone Remodeling by Isoflavone and 3,3′-Diindolylmethane in the Context of Prostate Cancer Bone Metastasis

“…More importantly, we found that TGF-β could up-regulate the expression of RANKL, leading to the differentiation of osteoclasts. These results are also consistent with report from other investigator [31], suggesting that the activation of TGF-β, which is commonly seen in advanced PCa, could stimulate the differentiation of osteoclasts, leading to bone resorption and bone remodeling. Moreover, it is well known that TGF-β could also induce EMT [34], which facilitates PCa progression including invasion and bone metastasis.…”

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