Role of endothelin-1 in osteoblastic bone metastases

Research output: Contribution to journalArticle

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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 (ETA), but not ETB, receptors. Mice inoculated with the ZR-75-1 breast cancer line and treated with a selective ETA 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. ETA receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases due to breast or prostate cancer.

Original languageEnglish (US)
Pages (from-to)779-784
Number of pages6
JournalCancer
Volume97
Issue number3 SUPPL.
StatePublished - Feb 1 2003
Externally publishedYes

Fingerprint

Endothelin-1
Neoplasm Metastasis
Bone and Bones
Osteogenesis
Breast Neoplasms
Neoplasms
Osteoblasts
Endothelin A Receptors
Conditioned Culture Medium
Tumor Burden
Skull
Nude Mice
Prostatic Neoplasms
Growth
atrasentan

Keywords

  • Bone metastasis
  • Breast cancer
  • Endothelin
  • Osteoblast
  • Prostate cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Role of endothelin-1 in osteoblastic bone metastases. / Guise, Theresa; Yin, Juan Juan; Mohammad, Khalid.

In: Cancer, Vol. 97, No. 3 SUPPL., 01.02.2003, p. 779-784.

Research output: Contribution to journalArticle

Guise, T, Yin, JJ & Mohammad, K 2003, 'Role of endothelin-1 in osteoblastic bone metastases', Cancer, vol. 97, no. 3 SUPPL., pp. 779-784.
Guise, Theresa ; Yin, Juan Juan ; Mohammad, Khalid. / Role of endothelin-1 in osteoblastic bone metastases. In: Cancer. 2003 ; Vol. 97, No. 3 SUPPL. pp. 779-784.
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N2 - 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 (ETA), but not ETB, receptors. Mice inoculated with the ZR-75-1 breast cancer line and treated with a selective ETA 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. ETA receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases due to breast or prostate cancer.

AB - 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 (ETA), but not ETB, receptors. Mice inoculated with the ZR-75-1 breast cancer line and treated with a selective ETA 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. ETA receptor blockade may be useful for prevention and the treatment of osteoblastic bone metastases due to breast or prostate cancer.

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