We report here that myeloma cells bind fibronectin (FN) and vascular endothelial cell adhesion molecule-1 (VCAM-1), abundant ligands for very late antigen-4 (VLA-4) in the bone marrow with roles in myeloma growth, survival and extravasation,29, 30 and that cells expressing elevated levels of HPSE adopt an invasive phenotype on these ligands because of HPSE-mediated shedding of Sdc1, which couples vascular endothelial cell growth factor receptor-2 (VEGFR2) to VLA-4, activating its kinase activity. This evidence concerns the gene SDC1 and plasma cell myeloma.