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 protooncogene (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 HGF/SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34(+) cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET(-). c-MET expression was induced by PMA, ConA, HGF/SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non-Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET(+) B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by beta(1)-integrins alpha(4) beta(1) (VLA4) and alpha(5) beta(1) (VLA5) since blocking antibodies against beta(1)- (CD29), alpha(4)-(CD49d), or alpha(5)- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma 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 invasion assays HGF/SF had no effect on c-MET(-) cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET(+) B-lymphoma cells to FN and CN, mediated via beta(1)-integrins alpha(4) beta(1) and alpha(5) beta(1), and furthermore promoted migration and invasion. (C) 1997 by the American Society of Hematology.