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

Oncogene. 2006 Nov 16;25(54):7180-91. doi: 10.1038/sj.onc.1209699. Epub 2006 May 29.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism
  • Cell Proliferation
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Flow Cytometry
  • Gene Expression
  • Gene Expression Profiling
  • Hematopoietic Stem Cells / metabolism
  • Heparan Sulfate Proteoglycans / metabolism*
  • Humans
  • Ligands
  • Middle Aged
  • Multiple Myeloma / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Plasma Cells / metabolism
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Syndecan-1 / metabolism


  • Heparan Sulfate Proteoglycans
  • Ligands
  • RNA, Messenger
  • SDC1 protein, human
  • Syndecan-1
  • Epidermal Growth Factor
  • ErbB Receptors