Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells

Abstract

Nuclear factor-κB (NF-κB) transcription factors play a key role in the pathogenesis of multiple myeloma (MM). The survival, proliferation and chemoresistance of malignant plasma cells largely rely on the activation of canonical and noncanonical NF-κB pathways. They are triggered by cancer-associated mutations or by the autocrine and paracrine production of cytokines and growth factors as well as direct interaction with cellular and noncellular components of bone marrow microenvironment (BM). In this context, NF-κB also significantly affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which have a critical role in disease progression. Indeed, NF-κB transcription factors are involved in inflammatory signaling that alters the functional properties of these cells to support cancer evolution. Moreover, they act as regulators and/or effectors of pathways involved in the interplay between MSCs and MM cells. The aim of this review is to analyze the role of NF-κB in this hematologic cancer, focusing on NF-κB-dependent mechanisms in tumor cells, MSCs and myeloma-mesenchymal stromal cell crosstalk.

Keywords: NF-kappa B; mesenchymal stromal cells; multiple myeloma.

Figure 1

(A) Regulation of MM cell activity by NF-κB. Schematic representation of classical (on the left) and alternative (on the right) activation pathways of NF-κB signaling. Gain of functions (green) and loss of functions (red) mutations of the NF-κB pathway are indicated. (B) Regulation of MSCs activity by NF-κB. NF-κB-dependent inflammatory pathways initiated by TLR4 ligands and cytokines, such as TNF-α and IL-1β, characterize myeloma specific inflammatory MSCs (iMSC).

Figure 2

Role of NF-κB in the regulation of MM cell proliferation by MSCs. The survival and proliferation of malignant plasma cells in the bone marrow microenvironment is sustained by adhesive contacts and soluble factors produced by MSCs.

Figure 3

Role of NF-κB in the regulation of MM bone disease by MSCs. Main NF-κB dependent mechanisms responsible for increased osteoclastastogenesis and reduced osteoblastogenesis in MM. Osteoclasts (OCs); osteoblasts (OBs).

Figure 4

Role of NF-κB in the regulation of antimyeloma immune response by MSCs. Expression of immune-activating ligands MICA and PVR is regulated by cytokines released by MSCs.

Figure 5

Role of NF-κB in MM drug resistance. MSC-derived soluble factors involved in the induction of MM resistance to bortezomib (in gray) and IMiDs (in blue).