Page 1562 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 86 Plasma Cell Neoplasms 1389

by MM cells. These results also suggest angiogenesis as a potential dexamethasone and to a greater extent than that observed with IL-6.
therapeutic target and explain in part the efficacy of thalidomide and These results have provided evidence for IGF-1 as an important
lenalidomide. therapeutic target.
Activation of NFκB has been observed in MM cells, especially
following their interaction with BMSCs. A number of abnormalities
contributing to the dysregulation of NFκB and constitutive activa- Vascular Endothelial Growth Factor
10
tion of the noncanonical NFκB pathway have been described. The
NFκB pathway can be activated either by deletion of NFκB inhibi- VEGF is produced predominantly by myeloma cells, and its expres-
tors (such as TRAF3 or CYLD) or by activation of NFκB activators sion is enhanced by MM–BMSC interaction as well as by IL-6 and
(such as NFκB–inducing kinase [NIK] or CD40). Inactivating muta- CD40 activation. It has only modest proliferative effects on myeloma
tions of TRAF3 and/or elevated expression of NIK by genomic cells, but it is the major factor affecting myeloma cell migration as
alterations or protein stabilization have been described and may well as angiogenesis. VEGF mediates part of its activity via Flt-1
explain mechanisms whereby MM cells achieve autonomy from the phosphorylation and downstream activation of MEK and protein
bone marrow microenvironment. kinase Cα (PKCα) signaling. Although these data suggest VEGF as
a potential target, specific anti-VEGF therapeutics have not yet
yielded significant clinical responses in myeloma.
CYTOKINES

Myeloma cell growth, survival, antiapoptosis, and drug resistance are Transforming Growth Factor-β
in part mediated by a number of cytokines produced by MM cells as
well as BMSCs. In fact, the production of cytokines is significantly TGF-β does not have a direct effect on myeloma cells, but it has a
modulated by MM–BMSC interactions and includes IL-6, insulin- number of activities that indirectly affect the clinical presentation of
like growth factor 1 (IGF-1), VEGF, tumor necrosis factor-α (TNF- patients with myeloma. It is produced by MM cells and induces
α), transforming growth factor-β (TGF-β), IL-17, IL-21, C-X-C secretion of IL-6 by BMSCs. Importantly, it induces immunosup-
motif chemokine 12 ligand (CXCL-12), and others. 10 pression characteristic of myeloma and may also affect normal plasma
cell development and function, thereby contributing to suppressed
background immunoglobulin production in myeloma. It is also a
Interleukin 6 major cytokine that affects Th cell development, especially Tregs and
Th17 cells.
IL-6 is one of the most important cytokines mediating both growth
and survival of MM cells. IL-6 plays an important role in the terminal
differentiation and also the proliferation of normal plasmablasts. The Interleukin 17 and Proinflammatory Cytokines
IL-6 receptor is composed of an α chain (gp80) and a signal-
transducing β chain (gp130), which are expressed by MM cells. IL-6 Elevated levels of Th17 cells, along with increased levels of serum
binding to its receptor activates Ras/RAF/MEK/ERK, JAK/STAT, IL-17 and associated proinflammatory cytokines IL-21, IL-22, and
and PI3K/AKT signaling pathways, mediating growth, survival, and IL-23, are observed in patients with myeloma. IL-17 has multiple
drug resistance. The major source of IL-6 production is the bone effects in myeloma, including induction of myeloma cell growth;
marrow stroma, with myeloma cells contributing to a lesser extent. suppression of immune function, especially in association with IL-22;
IL-6 production is induced by MM–BMSC interactions as well as by and induction of bone disease by increasing OC number and func-
other cytokines, including TNF-α and VEGF, present within the tion. IL-17 also induces IL-6 production by BMSCs, thereby aug-
bone marrow milieu. IL-6 acts mainly in a paracrine fashion but also menting its myeloma growth-inducing effects. IL-17 triggers
has, to some extent, autocrine activity. IL-6 has a number of other phosphorylation of JAK1, STAT3, and ERK1/2. TNF-α upregulates
activities, including being responsible for a number of symptoms expression of both IL-21 and of IL-21 receptor (IL-21R), and IL-21
observed in patients, induces anemia and thrombocytosis, induces induces proliferation and inhibits apoptosis of myeloma cells inde-
regulatory T cells (Tregs) as well as T helper 17 (Th17) cells with pendent of IL-6 signaling.
associated immunosuppression, and mediates enhanced bone resorp-
tion by OCs. Additionally, IL-6 promotes thrombosis without
affecting fibrinolysis. It induces a prothrombotic state by increasing Other Cytokines and Chemokines
the expression of fibrinogen, factor VIII, and von Willebrand factor;
increases the production of platelets; and activates endothelial cells. Tumor Necrosis Factor-α
Importantly, it confers resistance to antitumor agents especially
dexamethasone. Myeloma cells shed IL-6Rα and soluble IL-6R, TNF-α is primarily a mediator of inflammation. It is produced by
which can transduce the response of myeloma cells to IL-6. High myeloma cells and has no significant direct effect on myeloma cells.
serum levels of IL-6 as well as IL-6R are predictive of a poor prognosis. However, it induces IL-6 production by BMSCs. Antibodies specifi-
Both IL-6 and IL-6R are thus therapeutic targets, and antibodies cally targeting TNF-α have not shown clinical activity. CXCL-12
targeting them are in advanced stages of clinical development. (SDF-1) is expressed by BMSCs, and its receptor CXCR4 is expressed
by myeloma cells. It induces only a minimal proliferative effect;
however, it plays a more important role in mediating migration.
Insulin-Like Growth Factor 1 HGF, through its receptor c-Met expressed on the majority of
myeloma cells, promotes cell invasion, migration, and proliferation.
IGF-1, similar to IL-6, is a mitogenic factor secreted by myeloma It also induces differentiation and proliferation of OCs and increases
cells and mediates growth and survival of myeloma cells through bone resorption in patients with myeloma.
activation of the PI3K and MAPK signaling pathways. IGF-1 recep-
tor is expressed by myeloma cells, and binding of IGF-1 to its receptor
activates both signaling pathways. IGF-1 also mediates adhesion and IMMUNE ENVIRONMENT
migration of myeloma cells via β 1 -integrin and upregulates FLIP,
XIAP, and A1/Bfl1, thereby further enhancing tumor cell growth and Significant immune dysfunction is observed in patients with MM
survival. A number of IGF-binding proteins have been described that involving both T-cell and B-cell function as well as abnormalities in
modulate IGF-1 activity. These molecular and signaling changes dendritic cell (DC), natural killer (NK) cell, and natural killer T
collectively lead to induction of drug resistance, especially to (NKT) cell activity. 12–14 Researchers in a recent study described the