Mechanisms ofpromoting the bone invasion of cancer cells by osteopontin

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We isolated the mouse osteopontin(OPN) gene and analyzed its structure and function. Furthermore, we generated transgenic(TG) mice expressing OPN under the control of the α1-anti-trypsin promoter. OPN contains a GRGDS integrin-binding domain and is shown to promote the adhesion and migration of cancer cells. Osteoclasts have been shown to bind to bone matrix via αvβ3 and bone sialoprotein for attachment.We analyzed the role of OPN under the infiltration and metastasis of cancer cells in vivo and in vitro. As a result1. Bone infiltration and lung metastasis of cancer cellsOPN-TG mice and wild-type mice were given subcutaneous or intra-gingival injections of B16 melanoma cells. There was no significant difference of tumor growth and invasion between two groups of mice. Unexpectedly, significant inhibition of lung metastases in OPN-TG mice was observed as compared with the wild-type mice. The iv. pre-administration of recombinant OPN significantly inhibited the lung metastases with melanoma cells. 2. Construction of recombinant proteins and synthetic peptides possessing a functional domain derived from OPN2. Construction of recombinant proteins and synthetic peptides possessing a functional domain derived from OPNTo construct a recombinant proteins, the GST-fusion DNAs encoding the putative functional fragments were made and transfected into E. coli. But, no production of protein was confirmed. We therefore made some peptides with or without an Arg-Gly-Asp sequence. In preliminary experiment, a significant reduction in the number of lung tumor colonies was observed at a peptide containing Arg-Gly-Asp sequence.