Bone marrow endothelial cells in multiple myeloma secrete CXC‐chemokines that mediate interactions with plasma cells

Abstract

SummaryBone marrow endothelial cells (EC) from patients with multiple myeloma (MM) were found to express and secrete higher amounts of the CXCchemokines CXCL8/interleukin (IL)-8, CXCL11/interferon-inducible T-cell alpha chemoattractant (I-TAC), CXCL12/stromal cell-derived factor (SDF)-1a, and CCL2/monocyte chemotactic protein(MCP)-1 than EC from human umbilical vein (HUVEC), considered as a healthy counterpart. Paired plasma cells and several MM cell lines expressed cognate receptors of each chemokine to a variable extent. When cells were exposed to chemokines, CXCL8/IL-8 and CXCL12/SDF-1a stimulated their proliferation and all chemokines stimulated cell chemotaxis. It is suggested that angiogenesis also favours MM progression through the release of CXC-chemokines.

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

“…Moreover, binding of plasma cells to BMSC triggers transcription and secretion by the latter of cytokines, such as IL-6 (Dankbar et al, 2000), IGF-1 (Ferlin et al, 2000) and VEGF (Gupta et al, 2001) and CXCL12/stromal cellderived factor-1a (SDF-1a) (Pellegrino et al, 2005), that mediate cell growth (IL-6, IGF-1, VEGF), survival (IL-6, IGF-1), drug resistance (IL-6, IGF-1, VEGF), migration (IGF-1, VEGF, MMPs, SDF-1a) and angiogenesis (VEGF) in the bone marrow. Endothelial cell of MM differ from HUVEC.…”

Targeted Inhibition of Multiple Proinflammatory Signalling Pathways for the Prevention and Treatment of Multiple Myeloma

“…Moreover, bone marrow endothelial cells are also shown to secrete CXCL12 and induce migration of myeloma cells towards the bone marrow endothelial cells. Thus, angiogenesis induced migration of myeloma cells is also mediated by CXCL12 chemokine [123]. The expression of CXCR4 was higher in bone marrow plasma cells of patients with myeloma than patients with MGUS.…”

“…Myeloma cells derived from patients with myeloma, as well as myeloma derived cell lines, express CXCR3 receptor and they respond to their ligands by inducing tyrosine kinase phosphorylation and secreting MMP2 and MMP9 [122]. Bone marrow endothelial cells also secrete CXC chemokines and certain myeloma cells expressing their cognate receptors migrate in response to these chemokines [123].…”

Neoplastic Plasma Cells Generate an Inflammatory Environment Within Bone Marrow and Markedly Alter the Distribution of T Cells Between Lymphoid Compartments

“…Elevated levels of several chemokines have previously been documented in MM and are thought to play a role in promoting MM proliferation and survival [27-29, 31, 32, 34, 36, 39, 40]. The source of these chemokines appears to derive from both the myeloma plasma cells and associated stromal cells [34,36,40,41]. As such, CXCL9 [42], CXCL12 [28] and CCL3 [43] have been shown to be produced by myeloma plasma cells whereas stromal cells have been shown to produce a range of chemokines, including CCL2, CCL7, CCL8 and CCL13 from osteoclasts [44], CXCL8, CXCL11, CXCL12 and CCL2 from endothelial cells and bone marrow fibroblasts producing CXCL12 [28].…”

“…The expression of CXC chemokines such as CXCL12 (SDF-1) and CXCL8 (IL-8) has been reported to be modulated in patients with MM [31,[33][34][35][36]. CXCL12 is the ligand for CXCR4 whereas CXCL8 binds to the CXCR1 and CXCR2 receptors.…”