Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis.
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.
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
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Meng
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
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Vander Ark
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
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Lee
Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI, USA.
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Hostetter
Samuel Oschin Comprehensive Cancer Institute and Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA.
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Bhowmick
Pancreatic Cancer Action Network, Washington, DC, USA.
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Matrisian
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
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Williams
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
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Miranti
Program for Skeletal Disease and Tumor Microenvironment, Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI, USA.
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Li
D000818:Animals; D000912:Antibodies, Neoplasm; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000912:Antibodies, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II