HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR PROMOTES ADHESION OF LYMPHOMA-CELLS TO EXTRACELLULAR-MATRIX MOLECULES VIA ALPHA(4)BETA(1) AND ALPHA(5)BETA(1) INTEGRINS

Hepatocyte growth factor (HGF)/scatter factor (SF) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogen e (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HG F/SF and c-MET also play a role in adhesion and invasion of human lymp homa cells. c-MET mRNA is expressed in hemopoietic cells, such as hemo poietic progenitor cells (CD34(+) cells) in bone marrow (BM) and mobil ized peripheral blood, immature B cells in cord blood and BM, and germ inal center B-centroblasts. In normal peripheral blood B cells, which are c-MET(-). c-MET expression was induced by PMA, ConA, HGF/SF, and E pstein-Barr virus (EBV) infection. Using immunohistochemistry, we dete cted c-MET on the cell surface of large activated centroblasts in lymp h nodes from patients with B-non-Hodgkin's lymphoma and Hodgkin's dise ase. In the latter group, c-MET expression correlated well with the pr esence of EBV. Because HGF/SF and c-MET promote metastasis of carcinom a cells, we studied the effects of c-MET stimulation by HGF/SF of B-ly mphoma cells on properties relevant for metastasis, ie, adhesion, migr ation, and invasion. HGF/SF stimulated adhesion of the c-MET(+) B-cell lines to the extracellular matrix molecules fibronectin (FN) and coll agen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by beta(1)-integr ins alpha(4) beta(1) (VLA4) and alpha(5) beta(1) (VLA5) since blocking antibodies against beta(1)- (CD29), alpha(4)-(CD49d), or alpha(5)- (C D49e) integrin subunits, completely reversed the effect of HGF/SF. Fur thermore, HGF/SF induced adhesion was abrogated by addition of geniste in, which blocks protein tyrosine kinases, including c-MET. Addition o f HGF/SF resulted in a sixfold increase in migration of c-MET B-lympho ma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET(+) B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and in vasion assays HGF/SF had no effect on c-MET(-) cell lines. In conclusi on, c-MET is expressed or can be induced on immature, activated, and c ertain malignant B cells. HGF/SF increased adhesion of c-MET(+) B-lymp homa cells to FN and CN, mediated via beta(1)-integrins alpha(4) beta( 1) and alpha(5) beta(1), and furthermore promoted migration and invasi on. (C) 1997 by the American Society of Hematology.