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

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-a 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.

Metastasis Suppressor Tetraspanin CD82/KAI1 Regulates Ubiquitylation of Epidermal Growth Factor Receptor

“…These ligand-HSPG interactions may either enhance or attenuate the activity of the receptors (20,21). Importantly, it has previously been reported that the activity of HB-EGF (but not EGF) is dependent on syndecans, the most prominent family of cell-associated proteoglycans (38,39). Therefore, one can envisage a scenario whereby CD82 and its tetraspanin partners (e.g., CD9, which is known to associate with syndecans (3,5)) facilitate formation of the tripartite EGFR-growth factor-HSPG complex, which activates not only receptor but also HSPG.…”

New Negative Feedback Regulators of Egfr Signaling inDrosophila

“…Some vertebrate EGF ligands are known to bind HSPGs, including some neuregulins (NRGs) and heparin-binding EGF (Pankonin et al 2005;Mahtouk et al 2006;Iwamoto et al 2010). The NRGs share structural similarity with Vn because both types of growth factors have an Ig domain in addition to the EGF domain .…”

Input of DNA Microarrays to Identify Novel Mechanisms in Multiple Myeloma Biology and Therapeutic Applications

“…However, although IL-6 is essential, it is not sufficient and additional factors, produced by the microenvironment or the tumor cells themselves, are required together with IL-6 to promote tumor growth (3). We and others have identified such factors, as for example insulin-like growth factor-I (4, 5), IFN-a (6), IL-10 (7), hepatocyte growth factor (8), Wnt family (9), and more recently members of the epidermal growth factor (EGF) family (10) and B-cell activating factor/a proliferation-inducing ligand (BAFF/APRIL; ref. 11).…”