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

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.

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“…Elevated expression levels of FGFR1 are characteristic of many aggressive metastatic cancers that have undergone EMT (41)(42)(43). Basal-like cell breast cancers display high levels of FGFR1 along with elevated FOXC1 expression (44,45).…”

Effects of metformin and phenformin on apoptosis and epithelial‐mesenchymal transition in chemoresistant rectal cancer

“…Transforming growth factor (TGF) β receptor type 2 (TGFBR2), a member of the TGF‐β/Smad pathway, is involved in tumorigenesis. The expression of TGFBR2 is altered in various malignancies, including metastatic breast cancer, CRC and prostate cancer . TGF‐β signaling is an important pathway contributing to cancer development and has various functions in the regulation of cell growth, differentiation, apoptosis, EMT, angiogenesis and metastasis in a cellular context‐dependent manner .…”

Paradoxical TGFβ and Therapeutic Strategies

“…Recent studies have showed that host immune cells play a critical role in switching the activity of TGFβ [20,21]. Genetic abrogation of TGFβ signaling specifically in myeloid cells resulted in reduction of bone and lung metastasis in an in vivo mouse model system [20,21]. These two studies have unequivocally suggested that specific targeting of TGFβ signaling in myeloid cells reduces tumor metastasis.…”

“…However, the precise molecular mechanisms determining when the TGFβ switches from a tumor suppressor to promoter poses a great challenge in the field. Recent studies have showed that host immune cells play a critical role in switching the activity of TGFβ [20,21]. Genetic abrogation of TGFβ signaling specifically in myeloid cells resulted in reduction of bone and lung metastasis in an in vivo mouse model system [20,21].…”