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Carcinogenesis Advance Access originally published online on May 9, 2003
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Carcinogenesis, Vol. 24, No. 8, 1317-1323, August 2003
© 2003 Oxford University Press

CANCER BIOLOGY

Growth and angiogenesis of human breast cancer in a nude mouse tumour model is reduced by NK4, a HGF/SF antagonist

Tracey A. Martin2, Christian Parr, Gaynor Davies, Gareth Watkins, Jane Lane, Kunio Matsumoto1, T. Nakamura1, Robert E. Mansel and Wen G. Jiang

Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
1 Division of Biochemistry, Department of Oncology, Biomedical Research Centre, Osaka University Medical School, Suita, Osaka, Japan

2 To whom correspondence should be addressed. Tel: +44 29 20744711; Fax: +44 20 20761723; Email: martinta1{at}cf.ac.uk

Hepatocyte growth factor/scatter factor (HGF/SF) is a cytokine primarily produced by stromal fibroblasts and is a known angiogenic and invasion-inducing factor. It is increased in patients with breast cancer. This study examined the effect of NK4, a newly described HGF/SF antagonist, on HGF/SF-promoted growth of a human breast cancer. Both in vitro (invasion and migration assays) and in vivo (murine tumour model) methods were used to ascertain the effect of NK4 on HGF/SF from two sources: human fibroblast-derived HGF/SF and recombinant HGF/SF. In the in vitro invasion assay and migration assay, both HGF/SF and human fibroblasts, which secrete bioactive HGF/SF, increased the invasiveness and migration of the breast cancer cells (MDA MB 231). NK4 significantly reduced this invasiveness and motility. In the animal model, tumour volume and weight was significantly reduced with addition of NK4. It also suppressed HGF/SF-induced growth and markedly retarded tumour growth induced by fibroblasts (MRC5), secreting bioactive HGF/SF. Tumour angiogenesis was assessed by immunohistochemical staining of primary tissue sections using VE-cadherin (an endothelial cell specific cell–cell adhesion molecule). Again, NK4 reduced the effects of both HGF/SF and fibroblasts. We conclude that NK4 has a significant effect on the growth of human breast tumours in nude mice, particularly when stimulated by HGF/SF or fibroblasts. This may occur by decreasing angiogenesis. This gives a clear indication of the therapeutic worth of NK4.


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