Abstract 4839: TGF-β signaling in osteoclasts promotes, but in osteoblasts inhibits prostate cancer induced bone lesions

Abstract

Abstract Bone is the only clinically detected metastatic site in advanced prostate cancer (PCa) patients. Bone metastases were found in 70% of patients who died of PCa. The mechanism of PCa bone metastasis is largely unknown, partially due to different types of bone lesions existing in the same patients. Transforming growth factor beta (TGF-β) is known to be abundant in the bone microenvironment and a key factor driving cancer cell colonization and proliferation in the bone, and inducing the bone lesion development. Previous studies have shown that blocking the pathway systemically or in cancer cells reduces the breast cancer and melanoma bone metastases in animal models, presenting an exciting target for cancer therapy. However, TGF-β is also directly affecting the proliferation and differentiation of all the cells in the bone microenvironment. Blocking TGF-β in bone metastases patients will only be possible until the cell specific contribution of TGF-β signaling in the bone microenvironment to cancer cells were further delineated. We hypothesized that cell specific TGF-β signaling in the bone microenvironment has a distinct role in PCa bone metastasis. Genetically engineered mouse (GEM) models were used to delineate the role of mesenchymal cell or myeloid cell specific TGF-β signaling on PCa-induced osteolytic bone lesion development. Lysozyme M promoter-driven Cre was used to induce the ablation of the TGF-β type II receptor (Tgfbr2) in mature macrophages, granulocytes and osteoclasts, thus to knockout TGF-β signaling in these cells [LysMcre/Tgfbr2floxE2/floxE2/Rosa26/Rag2-/- (Tgfb_off_OC)]. The collagen promoter-driven Cre was used to knockout TGF-β signaling in fibroblasts, chondrocytes and osteoblasts [ColcreERT/Tgfbr2floxE2/floxE2/Rosa26/Rag2-/- (Tgfb_off_OB)]. PC3 PCa cells were injected into the tibiae of the GEMs and their respective Cre- controlled mice. The host mice tibiae were imaged using Faxitron x-ray every week from 2 to 4 weeks post tumor injection; the bone lesion areas were measured and analyzed by Metamorph. We found that the osteolytic bone lesion development was significantly reduced in the Tgfb_off_OC mice compared to the control mice at 4 weeks post tumor inoculation (p<0.05). In contrast, PC3 cells in the Tgfb_off_OB mice compared to the control mice significantly promoted osteolytic bone lesion development started from 2 weeks and up to 4 weeks post tumor injections (p<0.05). All statistics were applied by student's T tests. These results suggest that TGF-β signaling activation is anti-osteolytic in osteoblasts, but pro-osteolytic in osteoclasts in this PC3 induced bone lysis models. Citation Format: Xiangqi Meng, Priscilla Lee, Xiaohong Li. TGF-β signaling in osteoclasts promotes, but in osteoblasts inhibits prostate cancer induced bone lesions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4839. doi:10.1158/1538-7445.AM2014-4839