Role of endothelin-1 in osteoblastic bone metastases

Abstract

BACKGROUND Certain solid tumors metastasize to bone and cause an osteoblastic response. The mechanisms by which tumor cells stimulate this new bone formation are not completely understood. METHODS The authors identified three breast cancer lines that cause osteoblastic metastases in female nude mice and provided evidence that tumor‐produced endothelin‐1 (ET‐1) mediates the osteoblastic response. RESULTS Tumor conditioned media, as well as exogenous ET‐1, stimulated osteoblast proliferation and new bone formation in cultures of mouse calvariae. These effects were blocked by antagonists of the endothelin A (ET_A), but not ET_B, receptors. Mice inoculated with the ZR‐75‐1 breast cancer line and treated with a selective ET_A receptor antagonist (ABT‐627) had significantly fewer osteoblastic bone metastases and less tumor burden compared with untreated mice. In contrast, there was no effect of ABT‐627 on osteolytic bone metastases caused by ET‐1‐negative breast cancer, MDA‐MB‐231. ABT‐627 had no effect on growth in vitro or at the orthotopic site of ZR‐75‐1 or MDA‐MB‐231 cells. CONCLUSIONS Collectively, the data suggested that tumor‐produced ET‐1 mediates osteoblastic bone metastases by stimulating osteoblast proliferation and new bone formation. ET_A receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases due to breast or prostate cancer. Cancer 2003;97(3 Suppl):779–84. © 2003 American Cancer Society. DOI 10.1002/cncr.11129