Abstract 1482: Role of TGF-beta signaling and mechanism of osteoblastic tumorigenesis in prostate cancer

Abstract

Abstract Prostate cancer is the second leading cause of cancer death in men with 80% of deaths occurring due to bone metastasis. Transforming growth factor-beta (TGFβ) signaling is important for the regulation of bone mass and matrix properties. The role of TGFβ signaling in prostate cancer-induced bone metastasis is unclear due in part to a lack of prostate cancer cell lines that can efficiently induce bone metastasis and osteoblastic lesions in animal models. We have previously shown that a newly established human prostate cancer cell line, PacMetUT1, produces a large amount of active TGFβ1 and induces extensive bone metastases in calvaria, rib, femur, and tibia when inoculated in the left cardiac ventricle of male nude mice. Experimental data from our lab demonstrated that stable knockdown of TGFβ1 using a short hairpin-RNA resulted in a decreased tumor incidence and bone formation when the cells were directly injected into the right tibias of male nude mice. Systemic administration of either a small inhibitor of TGFβ type I receptor kinase or a pan-TGFβ binding protein also decreased osteoblastic intratibial tumor lesions. However, the mechanism by which prostate cancer cells metastasize to bone and how they induce formation of osteoblastic lesions remains to be intensively investigated. We hypothesize that TGFβ and other growth factors released from tumor cells can induce aromatase gene expression and activity in bone cells leading to an enhanced estradiol synthesis which would lead to an increase in bone formation as estrogen is a known osteogenic factor. We examined the effect of TGFβ1 and BMP-4/7 treatment on aromatase expression in pre-osteoblastic cells in vitro. In vitro treatment with 5ng/ml of TGFβ1 and 25ng/ml of BMP-4/7 resulted in an increase in aromatase expression in 2T3, a mouse mesenchymal stem cell and in 63 year old male mesenchymal stem cells (MSC) at the protein level. Furthermore, TGFβ resulted in an induction of Smad-1/5 signaling pathway in these pre-osteoblastic cells. Transient knockdown of Smad-1/5 expression in male MSC by siRNA, resulted in a decreased aromatase expression. Our results demonstrate TGFβ to be a major driver of osteoblastic tumorigenesis in PacMetUT1 cells, and Smad-1/5-dependent aromatase upregulation by TGFβ superfamily ligands in pre-osteoblastic cells. Future studies will delineate whether the induction of aromatase mediates osteoblastic bone metastasis in vivo, and if combination treatment of TGFβ and aromatase inhibitors can be used as a novel therapeutic strategy for bone metastatic prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1482. doi:10.1158/1538-7445.AM2011-1482