ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling cascade for bone metastasis.
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 alpha (TGFalpha) 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.
Lu
Xin
X
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Wang
Qiongqing
Q
Hu
Guohong
G
Van Poznak
Catherine
C
Fleisher
Martin
M
Reiss
Michael
M
Massagué
Joan
J
Kang
Yibin
Y
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary*; D001842:Bone and Bones / Q000166:cytology / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction
D053244:Osteoprotegerin; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D053245:RANK Ligand; D004815:Epidermal Growth Factor; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D000077156:Gefitinib