title: Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma.
abstract: Inappropriate activation of MET, the receptor tyrosine kinase for hepatocyte growth factor (HGF), has been implicated in tumorigenesis. Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored. Here, we have examined a panel of 110 B-cell malignancies for MET expression, which, apart from MM (48%), was found to be largely confined to diffuse large B-cell lymphomas (DLBCLs) (30%). No amplification of the MET gene was found; however, mutational analysis revealed 2 germ-line missense mutations: R1166Q in the tyrosine kinase domain in 1 patient, and R988C in the juxtamembrane domain in 4 patients. The R988C mutation has recently been shown to enhance tumorigenesis. In MET-positive DLBCL cells, HGF induces MEK-dependent activation of ERK and PI3K-dependent phosphorylation of PKB, GSK3, and FOXO3a. Furthermore, HGF induces PI3K-dependent alpha4beta1 integrin-mediated adhesion to VCAM-1 and fibronectin. Within the tumor microenvironment of DLBCL, HGF is provided by macrophages, whereas DLBCL cells themselves produce the serine protease HGF activator (HGFA), which autocatalyzes HGF activation. Taken together, these data indicate that HGF/MET signaling, and secretion of HGFA by DLBCL cells, contributes to lymphomagenesis in DLBCL.
authors.affiliation: Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands. marcel.spaargaren@amc.uva.nl.
authors.forename: Esther P M
authors.initials: EP
authors.lastname: Tjin
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Groen
authors.forename: Irma
authors.initials: I
authors.lastname: Vogelzang
authors.forename: Patrick W B
authors.initials: PW
authors.lastname: Derksen
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Klok
authors.forename: Helen P
authors.initials: HP
authors.lastname: Meijer
authors.forename: Susanne
authors.initials: S
authors.lastname: van Eeden
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D002448:Cell Adhesion; D058534:Class I Phosphatidylinositol 3-Kinases; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018095:Germ-Line Mutation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008264:Macrophages; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D015347:RNA Probes; D012333:RNA, Messenger; D017978:Receptors, Growth Factor / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3; D017228:Hepatocyte Growth Factor; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D015347:RNA Probes; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D012697:Serine Endopeptidases; C499517:FOXO3 protein, human; C484760:PIK3CA protein, human; C491743:MET protein, human; C482125:MAP2K1 protein, human; C081092:HGF activator