Angiostatin inhibits bone metastasis formation in nude mice through a direct anti-osteoclastic activity.

Abstract

Bone is a very common metastatic site for breast cancer. In bone metastasis, there is a vicious circle wherein bone-residing metastatic cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone promote tumor growth. The contribution of tumor angiogenesis in the growth of bone metastases is, however, unknown. By using an experimental model of bone metastasis caused by MDA-MB-231/B02 breast cancer cells that quite closely mimics the conditions likely to occur in naturally arising metastatic human breast cancers, we demonstrate here that when MDA-MB-231/B02 cells were engineered to produce at the bone metastatic site an angiogenesis inhibitor, angiostatin, there was a marked inhibition in the extent of skeletal lesions. Inhibition of skeletal lesions came with a pronounced reduction in tumor burden in bone. However, although angiostatin produced by MDA-MB-231/B02 cells was effective at inhibiting in vitro endothelial cell proliferation and in vivo angiogenesis in a Matrigel implant model, we have shown that it inhibited cancer-induced bone destruction through a direct inhibition of osteoclast activity and generation. Overall, these results indicate that, besides its well known anti-angiogenic activity, angiostatin must also be considered as a very effective inhibitor of bone resorption, broadening its potential clinical use in cancer therapy.

• Authors: Olivier Peyruchaud, Claire-Marie Serre, Roisin NicAmhlaoibh, Pierrick Fournier, Philippe Clezardin
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 46 Pg. 45826-32 (Nov 14 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12954626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Drug Combinations
• Laminin
• Proteoglycans
• Vascular Endothelial Growth Factor A
• matrigel
• Angiostatins
• Collagen
• Luciferases
• beta-Galactosidase

Topics

• Angiostatins (metabolism, pharmacology)
• Animals
• Blotting, Western
• Bone Neoplasms (secondary)
• Bone and Bones (metabolism)
• Cell Division
• Cell Line, Tumor
• Collagen (metabolism)
• Drug Combinations
• Endothelium, Vascular (metabolism)
• Female
• Humans
• Immunohistochemistry
• Laminin (metabolism)
• Luciferases (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microcirculation
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Osteoclasts (metabolism)
• Proteoglycans (metabolism)
• Time Factors
• Transfection
• Vascular Endothelial Growth Factor A (metabolism)
• beta-Galactosidase (metabolism)