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.

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

“…The precursors of CAFs are resident fibroblasts and progenitor cells. BM infiltrating fibroblasts promote neovessel formation by the secretion of high amounts of growth factors and angiogenic cytokines, such as VEGF-A, FGF-2, tumor necrosis factor-alpha (TNF-α), urokinase, and matrix metalloproteinases–MMPs [ 7 , 9 , 13 , 40 , 41 , 42 , 43 ]. Moreover, fibroblasts synthesize inducible nitric oxide synthase, which increases blood flow [ 41 ].…”

“…MM PCs unbalance the osteoblasts/osteoclasts equilibrium and this induces bone disease [ 13 , 47 , 48 , 49 ]. In the BM niches, there is an interplay between MM PCs, osteoclasts, and vascular ECs [ 13 ].…”

“…MM PCs unbalance the osteoblasts/osteoclasts equilibrium and this induces bone disease [ 13 , 47 , 48 , 49 ]. In the BM niches, there is an interplay between MM PCs, osteoclasts, and vascular ECs [ 13 ]. This close link induces a vicious circle between angiogenesis, bone lysis, and favors BM myeloma cells survival and expansion [ 13 , 48 , 49 ].…”

“…MM-associated microenvironment modifications include BM neovessel formation for assembling the “vascular niche” and bone cell activation for the constitution of the “osteoblastic niche” [ 13 ]. In these two specialized niches, myelomatous PCs grow, survive, and are protected from external attacks [ 13 , 14 ]. The alterations occurring in these niches represent predisposing events that facilitate the survival and expansion of neoplastic PCs.…”

Emerging Insights on the Biological Impact of Extracellular Vesicle-Associated ncRNAs in Multiple Myeloma

“…Along with cancer cells, BMSCs may take part in the drug resistance process. BM stromal cells are involved both in the beginning and in the maintenance of the drug-resistant phenotype of MM cells [91][92][93].…”