ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis

Xin Lu, Qiongqing Wang, Guohong Hu, Catherine Van Poznak, Martin Fleisher, Michael Reiss, Joan Massagué, Yibin Kang

Research output: Contribution to journalArticle

216 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1882-1894
Number of pages13
JournalGenes and Development
Volume23
Issue number16
DOIs
StatePublished - 2009

All Science Journal Classification (ASJC) codes

  • Genetics
  • Developmental Biology

Keywords

  • Bone metastasis
  • Breast cancer
  • EGFR
  • Metalloprotease
  • Osteoclastogenesis

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