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. 2021 Feb 9;10:625199. doi: 10.3389/fonc.2020.625199

Figure 1.

Figure 1

Bone marrow interactions that promote myeloma growth and survival. Myeloma cells bind to the extracellular matrix (ECM) via integrins, proteoglycans, and hyaluronan receptors. They also directly bind to bone marrow stromal cell (BMSC) such as dendritic cells (DC) via the VCAM-VLA4, ICAM-LFA1, ICAM-MUC1, and CD80/86-CD28 axes. BMSC will produce the cytokines SDF1α, IL6, APRIL, BAFF, TNFα, IGF, HGF, and VEGF. In turn, myeloma cells secrete TGFβ and VEGF for BMSC. Myeloma cells promote osteoclast activation by secreting MIP1α/β and VEGF and by promoting BMSC secretion of IL1, IL6, TNFα, RANKL, MIP1α/β, SDF1, and PTHRP. They also prevent osteoblast differentiation by downregulating RUNX2 via direct binding of the VLA-VCAM axis and secretion of DKK1 and IL3. They also secrete sFRP-2 which also suppresses osteoblast differentiation. Osteoclasts produce IL6 and CHSY1 to promote myeloma cell survival. Myeloma cells induce angiogenesis in the bone marrow by secreting HGF, bFGF, VEGF, Ang-2, cleaved syndecan-1 (SDC1), and TGFβ. They also promote BMSC secretion of HGF, VEGF, and IL8. Endothelial cells produce IL6 and IGF1 to influence myeloma cell survival. Myeloma cells promote an immunosuppressive environment by inhibiting T cell function through production of TGFβ, PD-L1, LAG3, TIM3, and IL10. They also signal to BMSC to produce IL5, IL6, TNFα, and IDO.