Fig. 2.

Role of CXCR4-CXCL12 axis in the possible signalling events in multiple myeloma (MM). MM cells express high levels of CXCR4 and interact with CXCL12 expressing BMSCs and localize across the endothelium lining the BM. This interaction upregulates cytokine secretion from both BMSCs and MM cells and upregulates the expression of adhesion molecules like VLA-4 and LFA-1 which are present on the surface of MM cells to VCAM-1 and ICAM-1, respectively, which are expressed on BMSCs. A. CXCR4-CXCL12 interaction leads to receptor internalization from the surface to the subcellular location that can activate different signaling cascades that can be associated with MM cell stemness, survival, proliferation, migration and metastasis. B. CXCR4 is desensitized through arrestin mediated internalization and lysosomal degradation followed by ubiquitination. MM cell adherence and localization to BMSCs upregulates the expression of a. VEGF, HGF, IL-6, TNFα all of which along with other cytokines and growth factors associate both homing and proliferation of MM cells through promoting the expression of integrin molecules; b. CXCL12 is also upregulated which leads to more VEGF and IL-6 expression to further promote enhanced CXCL12 expression by BMSCs and enhanced homing process. c. High CXCL12 and its associated cytokines and growth factors lead to overproduction of osteoclasts, where the process to inhibit osteoclastogenesis by OPG secreted from both osteoblasts and BMSCs is downregulated. Also, CXCR4-CXCL12 interaction through promoting MM cell adherence to BMSCs, enhances RANKL production which further suppress OPG production. d. Osteoblastogenesis is inhibited due to secretion of HGF from BMSCs. 1. Imbalanced osteoclast and osteoblast activity leads to the continuous homing-egression of MM cells into the circulation which is regulated by CXCR4 signaling. 2. Hypoxic BM microenvironment in association with CXCR4 over-expression by the MM cells lead to enhanced expression of EMT related genes (Twist, Slug, Snail) and reduced E-cadherin expression that further enhance de-adhesion and egression of MM cells into circulation through acquisition of 3. EMT phenotype followed by 3′. aggressive MM cell features with enhanced metastatic potential. 4. MM cells secrete IL-3 that also inhibit osteoblastogenesis. 5. CD138 expressed on the surface off MM cells can bind OPG to prevent its inhibitory effect on RANKL function. This higher RANKL/OPG ratio leads to osteoclast differentiation that promotes osteolysis and hypercalcemia. 6. MM cell interaction with BMSCs leads to VEGF, HGF, IL-6, TNFα overexpression by MM cells which are involved in both 6′′. osteoclastogenesis and 6′. angiogenesis. The complex interaction of MM cells with different cytokines, cellular components, extracellular matrix proteins along with MMPs can promote both, angiogenesis and aggressive metastatic behavior. I. Expansion and colonization of aggressive MM cells to secondary metastatic sites is associated by higher CXCL12 gradient that promotes CXCR4-positive MM cell migration and II. homing from the primary tumor sites. Overall, the net result of all these complex interactions is tumor expansion and MM progression.