Abstract
Multiple myeloma arises when malignant plasma cells invade and form multiple tumors in the bone marrow. High levels of heparanase (HPSE) correlate with poor prognosis in myeloma patients. A likely target of the enzyme is the heparan sulfate (HS) proteoglycan syndecan-1 (Sdc1, CD138), which is highly expressed on myeloma cells and contributes to poor prognosis in this disease. We find that HPSE promotes an invasive phenotype mediated by the very late antigen-4 (VLA-4, or α4β1 integrin) in myeloma cells plated on either fibronectin (FN) or vascular endothelial cell adhesion molecule-1 (VCAM-1), ligands that are prevalent in the bone marrow. The phenotype depends on vascular endothelial cell growth factor receptor-2 (VEGFR2), which is aberrantly expressed in myeloma, and is characterized by a highly protrusive lamellipodium and cell invasion. HPSE-mediated trimming of the HS on Sdc1 and subsequent matrix metalloproteinase-9-mediated shedding of the syndecan exposes a juxtamembrane site in Sdc1 that binds VEGFR2 and VLA-4, thereby coupling VEGFR2 to the integrin. Shed Sdc1 can be mimicked by recombinant Sdc1 ectodomain or by a peptide based on its binding motif, which causes VLA-4 to re-orient from the lagging edge (uropod) to the leading edge of migrating cells, couple with and activate VEGFR2. Peptides (called 'synstatins') containing only the VLA-4 or VEGFR2 binding sites competitively inhibit invasion, as they block coupling of the receptors. This mechanism is also utilized by vascular endothelial cells, in which it is also activated by HPSE, during endothelial cell tube formation. Collectively, our findings reveal for the first time the mechanism through which HPSE modulates Sdc1 function to promote both tumor cell invasion and angiogenesis, thereby driving multiple myeloma progression. The inhibitory synstatins, or inhibitors of HPSE enzyme activity, are likely to show promise as therapeutics against myeloma extravasation and spread.
Highlights
Multiple myeloma, a disease in which malignant plasma cells form disruptive bone tumors, is the second most prevalent hematologic malignancy in the United States.[1,2] The emergence of new therapies has greatly improved survival rates in myeloma patients.[2]
Adhesion and spreading of CAG cells on FN or vascular endothelial cell adhesion molecule-1 (VCAM-1) is enhanced by HPSE Prior work using CAG myeloma cells as a model for tumor formation in vivo has revealed a strong correlation between tumor growth and expression of HPSE and Sdc1.4,6,8,11,15 To identify a potential link between these two effectors, we examined the effects of high HPSE expression on CAG adhesion and motility on FN or VCAM-1, two ligands enriched in the bone marrow that are the peptide, whereas α3β1 integrin depends on QGAT at the C-terminus.[25]
Poor outcome in multiple myeloma is linked to high expression of HPSE and correspondingly high serum levels of shed Sdc1.6,10–12,15,21 Here, we show using myeloma cells, and extending the finding to endothelial cells as well, that an active motif in shed Sdc[1] promotes an invasive phenotype by coupling vascular endothelial cell growth factor receptor-2 (VEGFR2) to very late antigen-4 (VLA-4)
Summary
A disease in which malignant plasma cells form disruptive bone tumors, is the second most prevalent hematologic malignancy in the United States.[1,2] The emergence of new therapies (for example, bortezomib and thalidomide) has greatly improved survival rates in myeloma patients.[2] these therapies slow rather than cure the disease and patients develop resistance and become refractory. Sdc[1] is highly expressed on malignant plasma cells and has a causal role in multiple myeloma.[8,9,10,11,12,13,14]
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