Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator.
Multiple myeloma (MM) is a common hematologic neoplasm consisting of malignant plasma cells, which expand in the bone marrow. A potential key signal in the evolution of MM is hepatocyte growth factor (HGF), which acts as a potent paracrine and/or autocrine growth factor and survival factor for MM cells. Proteolytic conversion of HGF into its active form is a critical limiting step in HGF/MET signaling. Here, we show that malignant MM plasma cells convert HGF into its active form and secrete HGF-activator (HGFA), a serine protease specific for HGF activation. By using serine protease inhibitors and neutralizing antibodies, we demonstrate that HGFA produced by the MM cells is responsible for their ability to catalyze HGF activation. We, therefore, suggest that autocatalyzation of HGF conversion by MM cells is an important step in HGF/MET-induced myeloma growth and survival, which may have implications for the management of this incurable form of cancer.
Tjin
Esther P M
EP
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Derksen
Patrick W B
PW
Kataoka
Hiroaki
H
Spaargaren
Marcel
M
Pals
Steven T
ST
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002384:Catalysis; D045744:Cell Line, Tumor; D002469:Cell Separation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D011233:Precipitin Tests; D012697:Serine Endopeptidases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D017077:Culture Media, Conditioned; D017228:Hepatocyte Growth Factor; C081092:HGF activator; D012697:Serine Endopeptidases