title: Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.
abstract: A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As amphiregulin (AREG) is another heparin-binding factor of the EGF family, we investigated its role in multiple myeloma (MM). Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells. AREG stimulated IL-6 production and growth of BM stromal cells. Using real-time reverse transcriptase-polymerase chain reaction, we found that MM cells expressed ErbB receptors and that AREG promoted their growth. Furthermore, PD169540 (a pan-ErbB inhibitor) and IRESSA (an ErbB1-specific inhibitor) induced apoptosis of primary myeloma cells from 10/14 and 4/14 patients, respectively, and there was a synergistic effect with dexamethasone. Altogether, our data provide strong evidence that AREG plays an important role in the biology of MM and emphasize the advantages of using ErbB inhibitors, which might target myeloma cells as well as the tumor environment.
authors.affiliation: INSERM U475 and Unit for Cellular Therapy, CHU Montpellier, Hôpital St Eloi, 34000 Montpellier, France.
authors.forename: Karène
authors.initials: K
authors.lastname: Mahtouk
authors.forename: Dirk
authors.initials: D
authors.lastname: Hose
authors.forename: Thierry
authors.initials: T
authors.lastname: Rème
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Michel
authors.initials: M
authors.lastname: Jourdan
authors.forename: Jérôme
authors.initials: J
authors.lastname: Moreaux
authors.forename: Geneviève
authors.initials: G
authors.lastname: Fiol
authors.forename: Marc
authors.initials: M
authors.lastname: Raab
authors.forename: Eric
authors.initials: E
authors.lastname: Jourdan
authors.forename: Véronique
authors.initials: V
authors.lastname: Grau
authors.forename: Marion
authors.initials: M
authors.lastname: Moos
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.forename: Marion
authors.initials: M
authors.lastname: Baudard
authors.forename: Jean François
authors.initials: JF
authors.lastname: Rossi
authors.forename: Friedrich W
authors.initials: FW
authors.lastname: Cremer
authors.forename: Bernard
authors.initials: B
authors.lastname: Klein
mesh_terms: D066258:Amphiregulin; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001854:Bone Marrow Cells; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077156:Gefitinib; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000970:Antineoplastic Agents; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib
references.citation: Blood. 1998 Jun 15;91(12):4727-37
references.pmid: 9616171
references.citation: Cancer Res. 2003 Sep 1;63(17):5218-23
references.pmid: 14500348
references.citation: Leukemia. 2000 Jan;14(1):188-97
references.pmid: 10637495
references.citation: Blood. 2002 Mar 1;99(5):1745-57
references.pmid: 11861292
references.citation: Nature. 1998 May 7;393(6680):83-5
references.pmid: 9590694
references.citation: Science. 2004 Jun 4;304(5676):1497-500
references.pmid: 15118125
references.citation: Cell Mol Life Sci. 2001 Aug;58(9):1189-205
references.pmid: 11577978
references.citation: Blood. 1994 Jun 15;83(12):3654-63
references.pmid: 8204890
references.citation: Nature. 1988 Mar 3;332(6159):83-5
references.pmid: 3258060
references.citation: EMBO J. 1997 Sep 15;16(18):5608-17
references.pmid: 9312020
references.citation: Hum Pathol. 1999 Dec;30(12):1405-11
references.pmid: 10667416
references.citation: Blood. 2001 Aug 1;98(3):771-80
references.pmid: 11468178
references.citation: Int J Hematol. 2003 Aug;78(2):106-13
references.pmid: 12953803
references.citation: Blood. 2002 Sep 15;100(6):2175-86
references.pmid: 12200383
references.citation: J Biochem. 1997 Aug;122(2):474-80
references.pmid: 9378729
references.citation: Adv Exp Med Biol. 2003;532:247-52
references.pmid: 12908563
references.citation: Endocr Relat Cancer. 2001 Sep;8(3):151-9
references.pmid: 11566606
references.citation: Exp Cell Res. 2003 Mar 10;284(1):2-13
references.pmid: 12648462
references.citation: J Cell Biol. 2000 May 29;149(5):995-8
references.pmid: 10831602
references.citation: Blood. 1995 May 1;85(9):2521-7
references.pmid: 7727780
references.citation: Clin Cancer Res. 2003 Oct 15;9(13):4653-65
references.pmid: 14581334
references.citation: Oncogene. 2002 Apr 11;21(16):2584-92
references.pmid: 11971193
references.citation: Exp Cell Res. 2003 Mar 10;284(1):99-110
references.pmid: 12648469
references.citation: J Immunol. 1991 Dec 15;147(12):4402-7
references.pmid: 1753108
references.citation: Blood. 2004 Mar 1;103(5):1829-37
references.pmid: 14576062
references.citation: Blood. 1989 Feb;73(2):517-26
references.pmid: 2783861
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6809-14
references.pmid: 9618494
references.citation: In Vitro Cell Dev Biol Anim. 1998 Feb;34(2):182-8
references.pmid: 9542658
references.citation: Blood. 1997 Nov 1;90(9):3482-95
references.pmid: 9345032
references.citation: Oncogene. 2003 Jun 5;22(23):3598-607
references.pmid: 12789268
references.citation: J Cell Physiol. 1997 Jun;171(3):291-8
references.pmid: 9180898
references.citation: Cell Death Differ. 2000 Dec;7(12):1244-52
references.pmid: 11175262
references.citation: Cancer Res. 2001 Jan 1;61(1):383-91
references.pmid: 11196191
references.citation: Blood. 1995 Oct 15;86(8):3123-31
references.pmid: 7579407
references.citation: Blood. 1993 Dec 15;82(12):3712-20
references.pmid: 8260708
references.citation: Cytokine Growth Factor Rev. 2000 Dec;11(4):335-44
references.pmid: 10959080
references.citation: N Engl J Med. 2004 May 20;350(21):2129-39
references.pmid: 15118073
references.citation: Nat Rev Mol Cell Biol. 2003 Dec;4(12):926-37
references.pmid: 14685171