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

Cancer Lett. 2018 Apr 1;418:109-118. doi: 10.1016/j.canlet.2018.01.018. Epub 2018 Jan 11.

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 (Tgfbr2Col1CreERT KO) or in osteoclasts (Tgfbr2LysMCre KO). We found that PCa-induced bone lesion development was promoted in the Tgfbr2Col1CreERT KO mice, but was inhibited in the Tgfbr2LysMCre KO mice, relative to their respective control Tgfbr2FloxE2 littermates. Since metastatic PCa cells attach to osteoblasts when colonized in the bone microenvironment, we focused on the mechanistic studies using the Tgfbr2Col1CreERT KO mouse model. We found that bFGF was upregulated in osteoblasts from PC3-injected tibiae of Tgfbr2Col1CreERT 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 Tgfbr2Col1CreERT 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / secondary
  • Cell Line, Tumor
  • Fibroblast Growth Factor 2 / metabolism*
  • Humans
  • Male
  • Mice, Knockout
  • Osteoblasts / metabolism*
  • Osteoclasts / metabolism
  • PC-3 Cells
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Receptor, Transforming Growth Factor-beta Type II / metabolism*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*
  • Transplantation, Heterologous

Substances

  • Transforming Growth Factor beta
  • Fibroblast Growth Factor 2
  • Receptor, Transforming Growth Factor-beta Type II
  • Tgfbr2 protein, mouse