Loss of TGF-β signaling in osteoblasts increases basic-FGF and promotes prostate cancer bone metastasis

Abstract

TGF-β plays a central role in prostate cancer (PCa) bone metastasis, and it is crucial to understand the bone cell-specific role of TGF-β signaling in this process. Thus, we used knockout (KO) mouse models having deletion of the Tgfbr2 gene specifically in osteoblasts (Tgfbr2^Col1CreERT KO) or in osteoclasts (Tgfbr2^LysMCre KO). We found that PCa-induced bone lesion development was promoted in the Tgfbr2^Col1CreERT KO mice, but was inhibited in the Tgfbr2^LysMCre KO mice, relative to their respective control Tgfbr2^FloxE2 littermates. Since metastatic PCa cells attach to osteoblasts when colonized in the bone microenvironment, we focused on the mechanistic studies using the Tgfbr2^Col1CreERT KO mouse model. We found that bFGF was upregulated in osteoblasts from PC3-injected tibiae of Tgfbr2^Col1CreERT KO mice and correlated with increased tumor cell proliferation, angiogenesis, amounts of cancer-associated fibroblasts and osteoclasts. In vitro studies showed that osteoblastogenesis was inhibited, osteoclastogenesis was stimulated, but PC3 viability was not affected, by bFGF treatments. Lastly, the increased PC3-induced bone lesions in Tgfbr2^Col1CreERT KO mice were significantly attenuated by blocking bFGF using neutralizing antibody, suggesting bFGF is a promising target inhibiting bone metastasis.

Keywords: Osteoblasts; Osteoclasts; Prostate cancer bone metastasis; TGF-β signaling; TGF-β type II receptor (TGFBR2); bFGF.