Cytokines and signal transduction in multiple myeloma

Abstract

Multiple Myeloma (MM) is diagnosed in 15,000 new individuals each year. The median survival has been prolonged from 3-4 to 7 years, especially in patients less than age 50 [1-3]. Despite recent advances including biological agents bortezomib, thalidomide, and lenalidomide, MM remains incurable due to the development of drug resistance, which manifests as relapsed/refractory disease [4, 5]. The molecular and cellular mechanisms whereby MM cells evade drug-induced cytotoxicity and acquire drug-resistant phenotypes include interaction of MM cells with cellular components within the bone marrow (BM) microenvironment [5]. MM cells predominantly reside in the BM and adhere both to the extracellular matrix (ECM) proteins and BM stromal cells (BMSCs) due to binding via adhesion molecules. This interaction between tumor cells and BMSCs not only localizes tumor cells in the BM, but also confers protection against apoptosis and triggers secretion of cytokines mediating autocrine [6, 7] and paracrine [8-11] growth of MM cells. Examples of cytokines include IL-6, IL-21, vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), B-cell stimulating factor 3 (BSF-3), tumor necrosis factor-α (TNF-α), stromal cell-derived factor 1α (SDF-1α), and fibroblast growth factor (FGF). Importantly, new and effective therapeutic strategies have been derived based upon targeting these cytokines and their signaling cascades both in MM cells and in the BM microenvironment. This chapter reviews the role of various cytokines in the biology of MM, as well as novel therapies that overcome cytokine-mediated growth, survival, migration, and drug-resistance.