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. 2021 Jan 9;13(2):217. doi: 10.3390/cancers13020217

Figure 1.

Figure 1

Malignant plasma cell trafficking events in multiple myeloma (MM) development. MM plasma cells reach the bone marrow (BM) niche through sinusoids, proliferate favored by the tumor microenvironment (TME) and, occasionally, egress to the circulation causing extramedullary disease. Homing: The interaction of the CXCL12 chemokine with its CXCR4 receptor, mediates homing, lodging and retention of both normal and malignant plasma cells into the BM. CXCL12–CXCR4 interaction upregulates the activity of the α4β1 integrin, allowing high binding to its ligand VCAM-1 expressed on the BM microvasculature. Other important adhesion molecules mediating MM cell homing into the BM are the α4β7 integrin, a receptor for MAdCAM-1 and fibronectin, and PSGL-1 which interacts with P- and E-selectin expressed on the endothelial cell surface. MM cell survival and proliferation: Inside the BM milieu, BM mesenchymal stromal cells (BMSC) secrete high levels of CXCL12 that, along with α4β1, α4β7, and αLβ2 integrins, as well as CD44, are important for anchoring and retention of MM cells into BM niches. During this stage, survival and proliferation of malignant plasma cells is contributed by two main soluble mediators, a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF), which bind B-cell maturation antigen (BCMA) in the cancer cell surface, and IL-6, whose receptor is also expressed on MM cells. In MM patients there is a pathological osteolineage imbalance with reduced osteoblasts in favor of osteoclasts which produce lytic lesions. BM osteoblastic niche facilitates the dormancy of MM cells, while osteoclasts induce MM cell reactivation. Extramedullary disease: In this context, cancer cells become independent from the TME, and CXCR4 function or expression is downregulated, an event that also occurs after bortezomib (BTZ) treatment. Macrophage migration inhibitory factor (MIF) can also bind to CXCR4, inducing the expression of adhesion molecules. Expression of CCR1 chemokine receptor is linked to MM plasma cell circulation.