ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis Journal Article
| Authors: | Lu, X.; Wang, Q.; Hu, G.; Van Poznak, C.; Fleisher, M.; Reiss, M.; Massague, J.; Kang, Y. |
| Article Title: | ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis |
| Abstract: | Bone metastasis is mediated by complex interactions between tumor cells and resident stromal cells in the bone microenvironment. The functions of metalloproteinases in organ-specific metastasis remain poorly defined despite their well-appreciated role in matrix degradation and tumor invasion. Here, we show a mechanism whereby two distinct metalloproteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1) and matrix metalloproteinase-1 (MMP1), orchestrate a paracrine signaling cascade to modulate the bone microenvironment in favor of osteoclastogenesis and bone metastasis. Proteolytic release of membrane-bound epidermal growth factor (EGF)-like growth factors, including Amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor α (TGFα) from tumor cells suppress the expression of osteoprotegerin (OPG) in osteoblasts and subsequently potentiate osteoclast differentiation. EGF receptor (EGFR) inhibitors block osteolytic bone metastasis by targeting EGFR signaling in bone stromal cells. Furthermore, elevated MMP1 and ADAMTS1 expression is associated with increased risk of bone metastasis in breast cancer patients. This study established MMP1 and ADAMTS1 in tumor cells, as well as EGFR signaling in osteoblasts, as promising therapeutic targets for inhibiting bone metastasis of breast cancer. © 2009 by Cold Spring Harbor Laboratory Press. |
| Keywords: | signal transduction; epidermal growth factor; controlled study; protein expression; bone neoplasms; bone tumor; osteolysis; unclassified drug; human cell; genetics; cancer risk; nonhuman; bone metastasis; drug targeting; cell proliferation; mouse; animal; cytology; metabolism; animals; mice; animal tissue; metastasis; breast cancer; gene expression; cell growth; protein kinase inhibitor; protein degradation; protein targeting; cell line; animal experiment; animal model; cell differentiation; drug effect; enzymology; pathology; breast neoplasms; protein kinase inhibitors; gene expression regulation; cancer inhibition; gene expression regulation, neoplastic; nude mouse; mice, nude; breast tumor; gefitinib; tumor cell; bone; paracrine signaling; microenvironment; osteoclast; bone and bones; gene silencing; egfr; stroma cell; quinazolines; interstitial collagenase; quinazoline derivative; osteoblast; osteoblasts; amphiregulin; metalloprotease; osteoclastogenesis; a disintegrin and metalloproteinase with thrombospondin motifs 1; epidermal growth factor receptor kinase inhibitor; heparin binding epidermal growth factor; metalloproteinase; osteoprotegerin; transforming growth factor alpha; adam protein; adamts1 protein, human; mmp1 protein, human; osteoclast differentiation factor; bone cell; adam proteins; matrix metalloproteinase 1; rank ligand |
| Journal Title: | Genes and Development |
| Volume: | 23 |
| Issue: | 16 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2009-08-15 |
| Start Page: | 1882 |
| End Page: | 1894 |
| Language: | English |
| DOI: | 10.1101/gad.1824809 |
| PUBMED: | 19608765 |
| PROVIDER: | scopus |
| PMCID: | PMC2725946 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 20" - "Export Date: 30 November 2010" - "CODEN: GEDEE" - "Source: Scopus" |
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389Massague -
312Fleisher -
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