Breaking Barriers: The Role of the Bone Marrow Microenvironment in Multiple Myeloma Progression

Abstract

Multiple myeloma (MM) is an incurable malignancy characterized by the proliferation of abnormal plasma cells within the bone marrow, followed by potential dissemination to extramedullary sites. The bone marrow barrier (BMB) plays a pivotal role in plasma cell homing and disease progression. Bone marrow endothelial cells (BMECs) and bone marrow stromal cells (BMSCs), through their interactions with MM cells, secrete adhesion molecules, angiogenic cytokines, anti-apoptotic factors, and growth-promoting signals that support MM cell survival and proliferation. This review examines the components of the BMB and the major pathways involved in MM pathogenesis. Targeting the interactions between MM cells and the BMB may offer novel therapeutic opportunities.

Keywords: bone marrow barrier; bone marrow endothelial cells; bone marrow stromal cells; multiple myeloma.

Figure 1

Key signaling pathways in multiple myeloma cell adhesion and extravasation into the bone marrow microenvironment. Surface molecules expressed on multiple myeloma (MM) cells and their corresponding ligands or receptors on bone marrow endothelial cells (BMECs) mediate critical signaling pathways that facilitate MM cell trafficking, adhesion, and survival. CD147 on MM cells binds extracellular cyclophilin A (CyPA), which interacts with β-catenin and promotes its association with TCF/LEF, leading to the transcriptional activation of CCND1, MYC, SNAI1, and VIM, thereby enhancing MM cell survival and adhesion. The chemokine receptor CXCR4 binds its ligand CXCL12, driving MM cell migration toward the bone marrow niche and activating p-ERK and p-AKT signaling pathways. Integrins α4β7 and VLA-4 on MM cells engage with MadCAM-1 and VCAM-1 on BMECs, respectively, triggering NF-κB activation and the subsequent upregulation of cytokines (IL-6), chemokines (CCL2), anti-apoptotic proteins (Bcl-2, Bcl-xL), and additional adhesion molecules (VCAM-1). PSGL-1 on MM cells interacts with P- and E-selectins on BMECs, mediating rolling, adhesion, and transendothelial migration, through phosphorylation of FAK, Src kinase, AKT, p38, and Syk. The Figure was generated using BioRender.com.