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

Oncogene volume 25, pages 7180–7191 (2006)Cite this article

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-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.

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Acknowledgements

This work was supported by grants from the Ligue Nationale Contre le Cancer (équipe labellisée), Paris, France, and from the Association Guillaume Espoir, St Genis Laval, France.

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Authors and Affiliations

  1. INSERM, U475, Montpellier, France

    K Mahtouk, T Rème, M Jourdan, J Moreaux, J De Vos & B Klein

  2. CHU Montpellier, Institute of Research in Biotherapy, France

    K Mahtouk, T Rème, J Moreaux, G Requirand, G Fiol, J De Vos & B Klein

  3. Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, INF410, Heidelberg, Germany

    F W Cremer, M Moos, H Goldschmidt & D Hose

  4. Clinical Hematology Department, CHU Montpellier, France

    M Baudard, P Quittet & J-F Rossi

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  1. K Mahtouk
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Correspondence to B Klein.

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Mahtouk, K., Cremer, F., Rème, T. et al. Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma. Oncogene 25, 7180–7191 (2006). https://doi.org/10.1038/sj.onc.1209699

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