II。The non-cellular component includes the extracellular matrix, oxygen concentration, as well as cytokines, growth factors, and chemokines produced and/or affected by the cellular component of the BM microenvironment .
The migration of the malignant plasma cells to specific BM niches, their adhesion to the BM microenvironment, and the egress or mobilization of some of these cells into the peripheral circulation to home to other new BM sites is an active dynamic process. The process of cell migration through the blood to the BM niches is termed homing . Homing and retention of normal and malignant plasma cells into the BM is mainly mediated by the interaction of chemokine receptor CXCR4 on malignant cell surface, with its ligand CXCL12. Other adhesion molecules of importance in mediating malignant plasma cells homing are the α4β7 integrin (MAdCAM-1 and fibronectin receptor), and CD44. The interaction of CXCL12 with CXCR4 upregulates the α4β1 integrin activity, allowing its binding to its ligand VCAM-1 expressed on the BM microvasculature. This event plays key role in malignant plasma cells recirculation. P and E-selectin and their ligands (P-selectin glycoprotein ligand-1, PSGL-1) expressed on the surface of malignant plasma cells also contribute to their attachment to the BM microvasculature .
Upon MM niche stabilization, malignant plasma cells reprogram the local BM microenvironment, to provide further expansion signals for malignant plasma cells, which gradually become independent from initial normal niche support . These responses occur through direct contact of malignant plasma cells with stromal, endothelial or osteolineage cells, as well as their stimulation by supportive cytokines . This adhesive interaction between malignant plasma cells and marrow cells microenvironment results in secretion of growth and/or antiapoptotic factors including interleukin -6, insulin-like growth factor -1, vascular endothelial growth factor (VEGF), tumor necrosis factor -α, stromal cell–derived factor (SDF) 1α, and B-cell activating factor (BAFF). These factors trigger multiple proliferative/antiapoptotic signaling cascades in malignant plasma cells: Ras/Raf/mitogen-activated protein kinase (MAPK) kinase (MEK)/extracellular signal-related kinase (ERK); Janus kinase (JAK) 2/signal transducers and activators of transcription (STAT)-3; phosphatidylinositide-3 kinase (PI3K)/Akt; nuclear factor (NF)–κB; Wnt and Notch .
E.g. tadalafil: it reduced MDSC function in relapsed/ refractory MM patients . PDE5 inhibitors downregulate arginase 1 and nitric oxide synthase-2 expression and reduce the suppressive machinery of tumor recruited MDSCs in murine tumor models .