Syndecan-1 and stromal HSPGs: key moderators of communication between myeloma plasma cells and the bone marrow niche

Abstract

Upon antigen recognition by the B-cell antigen receptor (BCR), B-cells differentiate into plasma cells, which represent the effector cells of the humoral immune system. However, in contrast to their B-cell precursors, plasma no longer express a cell-surface BCR and, hence, are deprived of the BCR-derived signals, which are crucial for survival throughout B-cell development. Instead, for their survival, long-lived plasma cells heavily rely on communication with the bone-marrow (BM) microenvironment, which provides adhesion-mediated as well as multiple soluble signals. Plasma cells acquire strong expression of the cell-surface heparan sulfate proteoglycan (HSPG) syndecan-1, a phenotypic hallmark of plasma cells and their malignant multiple myeloma (MM) counterparts. Our research addresses how syndecan-1, in concert with HSPGs in the bone marrow microenvironment, mediates homing and survival of normal plasma cells, and promotes MM growth, by co-opting growth an survival factors from the BM niche and targeting them to their cognate receptors. The crucial function of syndecan-1 and of stromal HSPGs in the communication of MM with the bone marrow niche, designates these molecules and their synthesis machinery as potential treatment targets. Various venues to target syndecan-1/HSPGs in MM are currently being explored in preclinical and clinical studies. van Andel et al. PNAS 114:376-381 (2017). Ren et al. Blood 131:982-994 (2018).