Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression

Abstract

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.

Keywords: Bone marrow microenvironment; Cells adhesion molecules; Extra-cellular vesicles; Mesenchymal stem cells; Multiple myeloma; Soluble factors; Tunnelling-nanotubes.

Figure 1

Schematic representation of the main factors involved in the bidirectional communication between multiple myeloma cells and cells in the bone marrow microenviroment (bone marrow mesenchymal stem cells, osteoclasts, osteoblast, etc.). The main signaling patwthays activated by these factors are also depicted (Created with Biorender.com). VEGF: Vascular endothelial growth factor; FGF: Fibroblast growth factors; HGF: Hepatocyte growth factor; OPN: Osteopontin; ECs: Endothelial cells; IL: Interleukin; SDF1α: Stromal cell derived factor 1α; TNF-α: Tumor necrosis factor-α; BAFF: B-cell activating factor; DKK-1: Dickkopf-1; MM: Multiple myeloma; BM-MSC: Bone marrow mesenchymal stem cells; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3; NFκΒ: Nuclear factor kappa-Β; PI3K: Phosphatidylinositol 3-kinase; RANKL: Receptor activator of NFκΒ ligand; Ang-1: angiopoietin-1; MEK: MAPK kinase; ERK: Extracellular signal regulated kinase; LIF1: Leukemia inhibitory factor-1. Created with BioRender.com.

Figure 2

Schematic representation of the main cell adhesion molecules in multiple myeloma cells and bone marrow mesenchymal stem cells. The main interactions between cell adhesion molecules (CAMs) of these two types of cells as well as the interactions of these CAMs with proteins of the extracellular matrix are displayed (Created with Biorender.com). ICAM-1: Intercellular adhesion molecule 1; VCAM-1: Vascular cell adhesion molecule-1; LFA-1: Leukocyte function-associated antigen 1; N-CAM: Neural cell adhesion molecule; VLA: Very late antigen. Created with BioRender.com.