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Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

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,...

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Main Authors: Mahtouk, Karène (Author) , Cremer, Friedrich Walter (Author) , Rème, T. (Author) , Jourdan, M. (Author) , Baudard, M. (Author) , Moreaux, J. (Author) , Requirand, G. (Author) , Fiol, G. (Author) , De Vos, J. (Author) , Moos, Marion (Author) , Quittet, P. (Author) , Goldschmidt, Hartmut (Author) , Rossi, J.-F. (Author) , Hose, Dirk (Author) , Klein, B. (Author)
Format: Article (Journal)
Language:English
Published: 29 May 2006
In: Oncogene
Year: 2006, Volume: 25, Issue: 54, Pages: 7180-7191
ISSN:1476-5594
DOI:10.1038/sj.onc.1209699
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/sj.onc.1209699
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/1209699
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Author Notes:K. Mahtouk, F.W. Cremer, T. Rème, M. Jourdan, M. Baudard, J. Moreaux, G. Requirand, G. Fiol, J. De Vos, M. Moos, P. Quittet, H. Goldschmidt, J.-F. Rossi, D. Hose and B. Klein
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Summary: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-α 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 105 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.
Item Description:Gesehen am 15.02.2022
Physical Description:Online Resource
ISSN:1476-5594
DOI:10.1038/sj.onc.1209699

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