Hepatocyte Growth Factor/Scatter Factor Promotes Adhesion of Lymphoma Cells to Extracellular Matrix Molecules Via α4β1 and α5β1 Integrins

Abstract

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 β1-integrins α4β1 (VLA4) and α5β1 (VLA5) since blocking antibodies against β1- (CD29), α4- (CD49d), or α5- (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 β1-integrins α4β1 and α5β1 , and furthermore promoted migration and invasion.

Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells

“…In the present study, results from RT-PCR and Northern blot analyses demonstrated the expression of c-met, encoding the receptor for HGF, during the course of BMMC maturation. This observation supports studies showing that Met expression is not necessarily restricted to epithelial cells and is consistent with studies demonstrating Met expression on hematopoietic cells of the erythroid lineage, immature B lymphocytes, and a human mast cell line [17,81,87,89]. HGF is known to induce movement of diverse cell types [11,38,66,74,86].…”

“…While both α and β subunits are required for the proliferative activity of HGF, its motogenic activity in stimulating cell movement appears to reside largely in the α subunit [8,26]. β1 Integrins appear to have a major role in mediating the effect of HGF on cell movement [40,81,87]. However, the effects of HGF on β1 integrin function may vary with the cell types involved.…”

“…However, the effects of HGF on β1 integrin function may vary with the cell types involved. Thus, HGF stimulated α4 and α5 integrin-mediated adhesive function of various B cell lines [81,87]. In comparison, stimulation of the migratory function of squamous carcinoma cell lines by HGF did not involve an effect on the level of adhesion to ECM proteins [40].…”

Effect of hepatocyte growth factor on early human haemopoietic cell development

“…An HGF/MET R autocrine growth loop was recently proposed to play a role in the pathogenesis of human myeloma (Boerset et al, 1996). Alternatively, MET R activation could also play an important role in regulation of adhesion and homing of lymphoma cells to extracellular matrix (Weimar et al, 1997). By such a mechanism, HGF/MET R might regulate the apoptotic behaviour of lymphoma cells.…”

“…Finally, HGF/MET R may be involved in the development of Kaposi's sarcoma (Naidu et al, 1994), and in regulating integrin-dependent adhesion of lymphoma cells (Weimar et al, 1997). Nevertheless, the ability of HGF to influence the cloning efficiency of normal human adult progenitors remains controversial.…”