Pathways of Angiogenic and Inflammatory Cytokines in Multiple Myeloma: Role in Plasma Cell Clonal Expansion and Drug Resistance

Abstract

Multiple myeloma (MM) is the second most common hematological malignancy, and despite the introduction of innovative therapies, remains an incurable disease. Identifying early and minimally or non-invasive biomarkers for predicting clinical outcomes and therapeutic responses is an active field of investigation. Malignant plasma cells (PCs) reside in the bone marrow (BM) microenvironment (BMME) which comprises cells (e.g., tumour, immune, stromal cells), components of the extracellular matrix (ECM) and vesicular and non-vesicular (soluble) molecules, all factors that support PCs’ survival and proliferation. The interaction between PCs and BM stromal cells (BMSCs), a hallmark of MM progression, is based not only on intercellular interactions but also on autocrine and paracrine circuits mediated by soluble or vesicular components. In fact, PCs and BMSCs secrete various cytokines, including angiogenic cytokines, essential for the formation of specialized niches called “osteoblastic and vascular niches”, thus supporting neovascularization and bone disease, vital processes that modulate the pathophysiological PCs–BMME interactions, and ultimately promoting disease progression. Here, we aim to discuss the roles of cytokines and growth factors in pathogenetic pathways in MM and as prognostic and predictive biomarkers. We also discuss the potential of targeted drugs that simultaneously block PCs’ proliferation and survival, PCs–BMSCs interactions and BMSCs activity, which may represent the future goal of MM therapy.

Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition

“…The presented cases by us and others ( 3 , 4 , 12 , 19 – 21 ) support the use of JAK-inhibitors as an effective targeted therapy for patients with SPENCDI and severe cytopenias. Lack of effective biomarkers to capture the clinical response to JAK-inhibitors (e.g.…”

“…Both parents were identified as heterozygous asymptomatic carriers of one of the variants ( Figures 2B, C ; Supplementary Materials ; Supplementary Table 1 ). Based on the favorable therapeutic response of other patients with type I interferonopathies to JAK inhibitors ( 3 , 4 , 12 , 19 – 21 ), and the shared pathophysiologic hallmarks of SPENCDI with other type I interferonopathies ( 14 , 22 ), a therapeutic trial with the JAK1/JAK2 inhibitor ruxolitinib was initiated (0.4 mg/kg/day). Within a week from initiation of therapy, the patient reported significantly improved energy levels.…”

Anti-Angiogenic Activity of Drugs in Multiple Myeloma

“…During the transition from the avascular to the vascular phase, the activation of oncogenes such as c-myc, c-fos, c-jun, and Jun-B induces MM cells to secrete high amounts of pro-angiogenic cytokines, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), hepatocyte growth factor (HGF), angiopoietin-1, and insulin-like growth factor 1 (IGF-1) [ 13 , 14 , 15 ]. In turn, these cytokines act on BMSCs and on MM cells as well.…”

Molecular Features of the Mesenchymal and Osteoblastic Cells in Multiple Myeloma

“…In detail, IL-1β regulates the transcription of IL-6, which is mediated by upregulation of NF-kB activation. IL-6 stimulates the proliferation-inducing ligand ( APRIL ) and B-cell activating factor (BAFF) production, activating NF-kB/PI3K/AKT and MAPK pathways and thus promoting MM cell survival [ 62 ]. TNF-α also induces IL-6 secretion in BMSCs activating NF-kB [ 62 ].…”

“…IL-6 stimulates the proliferation-inducing ligand ( APRIL ) and B-cell activating factor (BAFF) production, activating NF-kB/PI3K/AKT and MAPK pathways and thus promoting MM cell survival [ 62 ]. TNF-α also induces IL-6 secretion in BMSCs activating NF-kB [ 62 ]. Lust et al demonstrated both in vivo and in vitro that blockade of IL-1β results in decreased IL-6 activity [ 63 , 64 ].…”