title: Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma.
abstract: The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro. To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-alpha were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) - neuregulin-1, amphiregulin, HB-EGF - promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10(5) molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.
authors.affiliation: INSERM, U475, Montpellier, France.
authors.forename: K
authors.initials: K
authors.lastname: Mahtouk
authors.forename: F W
authors.initials: FW
authors.lastname: Cremer
authors.forename: T
authors.initials: T
authors.lastname: Rème
authors.forename: M
authors.initials: M
authors.lastname: Jourdan
authors.forename: M
authors.initials: M
authors.lastname: Baudard
authors.forename: J
authors.initials: J
authors.lastname: Moreaux
authors.forename: G
authors.initials: G
authors.lastname: Requirand
authors.forename: G
authors.initials: G
authors.lastname: Fiol
authors.forename: J
authors.initials: J
authors.lastname: De Vos
authors.forename: M
authors.initials: M
authors.lastname: Moos
authors.forename: P
authors.initials: P
authors.lastname: Quittet
authors.forename: H
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: J-F
authors.initials: JF
authors.lastname: Rossi
authors.forename: D
authors.initials: D
authors.lastname: Hose
authors.forename: B
authors.initials: B
authors.lastname: Klein
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D053668:Syndecan-1 / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; D008024:Ligands; D012333:RNA, Messenger; C508241:SDC1 protein, human; D053668:Syndecan-1; D004815:Epidermal Growth Factor; D066246:ErbB Receptors