Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

Abstract

Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a "permissive" environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The "activated phenotype" of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.

Keywords: drug-resistance; microenvironment; multiple myeloma; plasma cells; stromal cells.

Figure 1

The “vascular niche”. In the pathologic bone marrow (BM), endothelial cells collaborate with other subtypes of stromal cells to assemble the vascular niche in which multiple myeloma (MM) plasma cells are stimulated to proliferate and survive, and are protected from the aggression of anti-myeloma drugs and immune system.

Figure 2

The “osteoblastic niche”. In the pathologic BM, resident macrophages and plasma cells induce the activation of osteoclasts and osteoclast precursors differentiation to assemble, with osteoblasts and the other subtypes of stromal cells, the osteoblastic niche in which MM plasma cells are stimulated to proliferate and survive, and are protected from the aggression of anti-myeloma drugs and the immune system.

Figure 3

Schematic of functional interactions of immune cells and with malignant plasma cells. The anti-myeloma activity of T cells, natural killer cells (NK), natural killer T cells (NKT), and γδ T cells against MM plasma cells is inhibited by malignant plasma cells via the activation of T regulatory cells (Tregs) and stimulation of myeloid-derived suppressor cells (MDSCs). Moreover, dendritic cell activity is also inhibited by Tregs and MDSCs. This makes the microenvironment immunologically permissive towards myelomatous proliferation and induces MM plasma cell escape from immune surveillance.