title: Cooperation between heparin-binding EGF-like growth factor and interleukin-6 in promoting the growth of human myeloma cells.
abstract: Interleukin-6 (IL-6) is a major survival and proliferation factor of human malignant plasma cells and IL-6 dependent myeloma cell lines can be obtained from patients with terminal disease. We show here that mutated diphtheria toxin, a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF), blocked the IL-6-induced growth of two myeloma cell lines (XG-1 and XG-14) and did not significantly affect that of two other cell lines (XG-6 and XG-13). The IL-6 mediated growth of myeloma cells was also inhibited by antibodies to ErbB1, a receptor for HB-EGF. The XG-1 and XG-14 cell lines that are sensitive to HB-EGF inhibitors overexpressed HB-EGF and EGF receptor (ErbB1) genes. They also overexpressed CD9, a tetraspanin that binds to the heparin-binding domain of HB-EGF and is critical for promoting ErbB1 activation by HB-EGF. The XG-6 and XG-13 myeloma cells that were not significantly sensitive to HB-EGF antagonists, poorly expressed HB-EGF, ErbB1 and CD9 genes or proteins. We demonstrated that recombinant HB-EGF supported the long-term growth of myeloma cells, as did IL-6. The myeloma cell growth factor activity of HB-EGF was completely inhited by antibodies to ErbB1, but also by antibodies to gp130 IL-6 transducer or to IL-6. These data indicate that in the XG-1 and XG-14 IL-6-dependent myeloma cell lines, the CD9/HB-EGF/erbB1 and the IL-6/IL-6R/gp130 pathways cooperate synergistically to trigger myeloma cell growth. They suggest that inhibitors of the EGF receptor or HB-EGF may be useful for inducing myeloma cell apoptosis in patients with multiple myeloma.
authors.affiliation: INSERM U475 and Unit for Cellular Therapy, CHU Montpellier, 99 Rue Puech Villa, 34197 Montpellier, France.
authors.forename: Yue Dan
authors.initials: YD
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Michel
authors.initials: M
authors.lastname: Jourdan
authors.forename: Guilhem
authors.initials: G
authors.lastname: Couderc
authors.forename: Zhao-Yang
authors.initials: ZY
authors.lastname: Lu
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Rossi
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D019898:Autocrine Communication; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000494:pharmacology*; D007700:Kinetics; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D012334:RNA, Neoplasm / Q000096:biosynthesis; D060245:Tetraspanin 29; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; C554869:CD9 protein, human; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012334:RNA, Neoplasm; D060245:Tetraspanin 29; D004815:Epidermal Growth Factor; D066246:ErbB Receptors