Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis

X. Meng, A. Vander Ark, P. Lee, G. Hostetter, N. A. Bhowmick, L. M. Matrisian, B. O. Williams, C. K. Miranti, X. Li

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Breast cancer (BCa) bone metastases cause osteolytic bone lesions, which result from the interactions of metastatic BCa cells with osteoclasts and osteoblasts. Osteoclasts differentiate from myeloid lineage cells. To understand the cell-specific role of transforming growth factor beta (TGF-β) in the myeloid lineage, in BCa bone metastases, MDA-MB-231 BCa cells were intra-tibially or intra-cardially injected into LysM Cre/Tgfbr2 floxE2/floxE2 knockout (LysM Cre/Tgfbr2 KO) or Tgfbr2 floxE2/floxE2 mice. Metastatic bone lesion development was compared by analysis of both lesion number and area. We found that LysM Cre/Tgfbr2 knockout significantly decreased MDA-MB-231 bone lesion development in both the cardiac and tibial injection models. LysM Cre/Tgfbr2 knockout inhibited the tumor cell proliferation, angiogenesis and osteoclastogenesis of the metastatic bones. Cytokine array analysis showed that basic fibroblast growth factor (bFGF) was downregulated in MDA-MB-231-injected tibiae from the LysM Cre/Tgfbr2 KO group, and intravenous injection of the recombinant bFGF to LysM Cre/Tgfbr2 KO mice rescued the inhibited metastatic bone lesion development. The mechanism by which bFGF rescued the bone lesion development was by promotion of tumor cell proliferation through the downstream mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-cFos pathway after binding to the FGF receptor 1 (FGFR1). Consistent with animal studies, we found that in human BCa bone metastatic tissues, TGF-β type II receptor (TβRII) and p-Smad2 were expressed in osteoclasts and tumor cells, and were correlated with the expression of FGFR1. Our studies suggest that myeloid-specific TGF-β signaling-mediated bFGF in the bone promotes BCa bone metastasis.

Original languageEnglish (US)
Pages (from-to)2370-2378
Number of pages9
JournalOncogene
Volume35
Issue number18
DOIs
StatePublished - May 5 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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