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

@article{citeulike:674626, 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-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.}, author = {Mahtouk, K. and Cremer, F. W. and Reme, T. and Jourdan, M. and Baudard, M. and Moreaux, J. and Requirand, G. and Fiol, G. and De Vos, J. and Moos, M. and Quittet, P. and Goldschmidt, H. and Rossi, J. F. and Hose, D. and Klein, B.}, citeulike-article-id = {674626}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/sj.onc.1209699}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/1209699a}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16732320}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16732320}, comment = {10.22.09 }, day = {29}, doi = {10.1038/sj.onc.1209699}, issn = {0950-9232}, journal = {Oncogene}, keywords = {hspg}, month = {May}, number = {54}, pages = {7180--7191}, posted-at = {2009-10-22 01:49:49}, priority = {0}, publisher = {Nature Publishing Group}, title = {Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma}, url = {http://dx.doi.org/10.1038/sj.onc.1209699}, volume = {25}, year = {2006} }

TY - JOUR ID - citeulike:674626 L3 - citeulike-article-id:674626 N2 - 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. IS - 54 JF - Oncogene SN - 0950-9232 EP - 7191 TI - Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma PB - Nature Publishing Group VL - 25 SP - 7180 KW - hspg N1 - 10.22.09 AU - Mahtouk, K AU - Cremer, FW AU - Reme, T AU - Jourdan, M AU - Baudard, M AU - Moreaux, J AU - Requirand, G AU - Fiol, G AU - De Vos, J AU - Moos, M AU - Quittet, P AU - Goldschmidt, H AU - Rossi, JF AU - Hose, D AU - Klein, B PY - 2006/05/29/ UR - http://dx.doi.org/10.1038/sj.onc.1209699 ER -