Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.
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.
Mahtouk
Karène
K
INSERM U475 and Unit for Cellular Therapy, CHU Montpellier, Hôpital St Eloi, 34000 Montpellier, France.
Hose
Dirk
D
Rème
Thierry
T
De Vos
John
J
Jourdan
Michel
M
Moreaux
Jérôme
J
Fiol
Geneviève
G
Raab
Marc
M
Jourdan
Eric
E
Grau
Véronique
V
Moos
Marion
M
Goldschmidt
Hartmut
H
Baudard
Marion
M
Rossi
Jean François
JF
Cremer
Friedrich W
FW
Klein
Bernard
B
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
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
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