A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Juan Juan Yin, Khalid S. Mohammad, Sanna M. Käkönen, Stephen Harris, J. Ruth Wu-Wong, Jerry L. Wessale, Robert J. Padley, I. Ross Garrett, John M. Chirgwin, Theresa A. Guise

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)10954-10959
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number19
DOIs
StatePublished - Sep 16 2003

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