Abstract
Multiple myeloma (MM) drug resistance (DR) is a multistep transformation process based on a powerful interplay between bone marrow stromal cells and MM cells that allows the latter to escape anti-myeloma therapies. Here we present an overview of the role of the bone marrow microenvironment in both soluble factors-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR), focusing on the role of new players, namely miRNAs, exosomes and cancer-associated fibroblasts.
Highlights
The BM microenvironment (BMME) includes a non-cellular compartment formed by extracellular matrix (ECM) proteins and soluble factors, and a rich cellular compartment constituted by hematopoietic cells and nonhematopoietic cells (fibroblasts, osteoblasts, osteoclasts, endothelial cells (ECs), endothelial progenitor cells (EPCs), pericytes, mesenchymal stem cells, mesenchymal stromal cells) (Figure 1)
environmentmediated drug resistance (EMDR) can be subdivided into: i) soluble factorsmediated resistance (SFM-drug resistance (DR)), which relies on cytokines, chemokines and growth factors, and ii) cell adhesionmediated resistance (CAM-DR) resulting from adhesion of tumor cells to bone marrow (BM) stromal cells or to ECM components
cancer-associated fibroblasts (CAFs), in turn, modify the BM stroma and influence chemotaxis, adhesion, proliferation, and apoptosis of MM cells through cell-to-cell contact www.impactjournals.com/oncotarget involving β3, β7, Very Late Activation Antigen (VLA)-4, VLA-5 and αVβ3 integrins expressed on MM cells and β3 and β7 integrins expressed on CAFs, and the secretion of TGF-β, HGF, IGF-1, IL-1, IL-6 and SDF-1α by both cell types [113]
Summary
The BMME includes a non-cellular compartment formed by extracellular matrix (ECM) proteins (laminin, fibronectin and collagen) and soluble factors (cytokines, growth factors, chemokines), and a rich cellular compartment constituted by hematopoietic cells (myeloid cells, T lymphocytes, B lymphocytes, NK cells) and nonhematopoietic cells (fibroblasts, osteoblasts, osteoclasts, endothelial cells (ECs), endothelial progenitor cells (EPCs), pericytes, mesenchymal stem cells, mesenchymal stromal cells) (Figure 1). Other integrins involved in CAM-DR are VLA-5 and β7: the former supports cells survival by up-regulating Bcl-2 expression [58], the latter increases MM cells adhesion, migration, and homing into BM, and reduces bortezomiband melphalan-induced apoptosis [46].
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