Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3

Abstract

The restricted bone marrow (BM) localisation of multiple myeloma (MM) cells most likely results from a specific homing influenced by chemotactic factors, combined with the proper signals for growth and survival provided by the BM microenvironment. In analogy to the migration and homing of normal lymphocytes, one can hypothesise that the BM homing of MM cells is mediated by a multistep process, involving the concerted action of adhesion molecules and chemokines. In this study, we report that primary MM cells and myeloma derived cell lines (Karpas, LP-1 and MM5.1) express the chemokine receptor CCR2. In addition, we found that the monocyte chemotactic proteins (MCPs) MCP-1, -2 and -3, three chemokines acting as prominent ligands for CCR2, are produced by stromal cells, cultured from normal and MM BM samples. Conditioned medium (CM) from BM stromal cells, as well as MCP-1, -2 and -3, act as chemoattractants for human MM cells. Moreover, a blocking antibody against CCR2, as well as a combination of neutralizing antibodies against MCP-1, -2 and -3, significantly reduced the migration of human MM cells to BM stromal cell CM. The results obtained in this study indicate the involvement of CCR2 and the MCPs in the BM homing of human MM cells.

Pre‐diagnostic blood immune markers, incidence and progression of B‐cell lymphoma and multiple myeloma: Univariate and functionally informed multivariate analyses

“…Although the markers identified in our study have been identified previously in clinical studies of MM or its precursor states ( i.e ., MGUS and SMM),45, 46, 47, 48, 49, 50 the direction of our findings is in general opposite to observations among subjects diagnosed with MM, where higher concentrations of these markers seems to be related to generally poorer disease outcome. The reason for this difference in direction of the effect is not known but may hint toward a preclinical deregulation of these important biological systems in subjects developing MM later in life which at the time of clinical manifestation reverse in overexpression.…”

Transendothelial Migration of Myeloma Cells Is Increased by Tumor Necrosis Factor (TNF)-α via TNF Receptor 2 and Autocrine Up-Regulation of MCP-1

“…In contrast to this clear chemokinetic effect, we could not confirm previously described chemotactic effects of MCP-1 on the myeloma cell lines (Ref. 21; data not shown).…”

“…Autocrine chemokine-loops in myeloma cells themselves might allow the cells to interfere with the chemokine gradients presented in the microenvironment. It has been reported that bone marrow stromal cells produce MCP-1, -2, and -3 (21). Our microarray data showed that U266 did not express MCP-2 and did not regulate MCP-3 and MCP-4 in response to TNF-␣, and that only MCP-1 was under the regulation of this cytokine.…”

“…Using microarray analysis, we found that TNF-␣-induced up-regulation of MCP-1 in myeloma cells correlated with migration, and blocking MCP-1 abrogated the enhanced migration induced by TNF-␣ stimulation. Migration of myeloma cells has previously been correlated with MCP-1, -2, and -3 in a mouse model and also in an in vitro model (21,30). In these investigations, the authors showed that MCP-1, MCP-2, and MCP-3, produced by endothelial cells and/or bone marrow stromal cells, promoted the directed migration of myeloma cells in response to chemotactic gradients, which would explain the restricted localization of the tumor.…”

Transforming Growth Factor β Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment

“…In this study, we show that SD-208 decreased IL-6 and VEGF secretion triggered by TGF-␤1 in a dose-dependent manner. SD-208 also inhibited TGF-␤1-triggered secretion of MCP-1, which binds to CCR2 on MM cells and mediates their migration to BMSCs (29), further suggesting that SD-208 decreases adhesion of MM cells to BMSCs and associated cytokine secretion.…”