Regulation of adhesion molecule integrins by membrane-bound proteinase ADAM

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ADAM is membrane-bound molecules composed of metalloproteinase and disintegrin. Expression of ADAM molecules of highly brain-metastatic subline and bone-metastatic subline from lung cancer cell EBC-1 cells are studied in order to clarify the implication of ADAM in cancer metastasis. As a result the expression level of ADAM9 mRNA was upregulated in brain-metastatic subline than those in bone-metastatic subline or parental cell line. Transfection of ADAM9 cDNA in kung cancer A549 cell resulted in increased NGF-stimulated invasive activity, elevated adhesion to brain tissue slices and upregulation of integrin a3b1 expression. There were no differences between transfectant and parental cell line in other integrin expression levels. When inoculated intravenously to the tail vein in skid mice, transfectants induced numerous lung and brain metastases. On the other hand parental cells or mock transfectant induced plenty of lung metastases, but not brain metastasis. These results suggested ADAM9 might play a role in brain metastasis of lung cancer.Transfection of ADAM9 cDNA in fibrosarcoma HT1080 cell was preformed and FACS analysis of each integrin expression showed disappearance of only integrin a4 in transfectants while parental cell or mock transfectant expressed integrin a4. Decreased adhesion of transfectants to CS-1 peptide or VCAM-1 (vascular cell adhesion molecule-1), both of which are ligands of integrin a4b1, was observed. Migratory or invasive activity to CS-1 or VCAM-1 was also reduced. When inoculated intravenously to tail vein of nude mice, parent cells induced a number of lung metastases but marked decreased lung metastases were found in transfectants. There were no differences in the tumor after subcutaneous injection.These data suggested ADAM9 might play some roles in integrin expression and also in cancer metastasis.