A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases.
Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation in vitro and osteoblastic metastases in vivo via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.
Yin
Juan Juan
JJ
Department of Molecular Medicine, University of Texas Health Science Center, Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX 78245, USA.
Mohammad
Khalid S
KS
Käkönen
Sanna M
SM
Harris
Stephen
S
Wu-Wong
J Ruth
JR
Wessale
Jerry L
JL
Padley
Robert J
RJ
Garrett
I Ross
IR
Chirgwin
John M
JM
Guise
Theresa A
TA
D001859:Bone Neoplasms / Q000556:secondary*; D016723:Bone Remodeling / Q000502:physiology; D019332:Endothelin-1 / Q000502:physiology*; D006801:Humans; D010006:Osteoblasts / Q000166:cytology*; D014407:Tumor Cells, Cultured
D019332:Endothelin-1