The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications

Hideshima, Teru; Chauhan, Dharminder; Schlossman, Robert; Richardson, Paul G.; Anderson, Kenneth C.

doi:10.1038/sj.onc.1204623

Cited by 362 publications

(319 citation statements)

References 45 publications

(37 reference statements)

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“…45 IL-6 and tumor necrosis factor-a have also been considered to be involved in the pathogenesis of monoclonal gammopathies. 46,47 However, in our experience, an increase in the serum levels of these two cytokines was not associated with a higher probability of malignant evolution. 48 What limits plasma cell growth and maintains a long-lasting MGUS state is uncertain.…”

Section: Mechanisms Of Progressionmentioning

confidence: 50%

Pathogenesis and progression of monoclonal gammopathy of undetermined significance

et al. 2008

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In Caucasians, monoclonal gammopathy of undetermined significance (MGUS) is an age-related condition with prevalence as high as 3% in persons older than 50 years. Compared with whites, blacks have around two-and threefold higher prevalence rates of MGUS and multiple myeloma (MM), respectively. Risk of progression from MGUS to MM has been found to be very similar in whites and blacks. On average, the transformation rate to a malignant monoclonal gammopathy is 1% per year, with the mechanisms of progression likely related to bone marrow microenvironment and/or the cytokine network. Overall, the actuarial probability of progression at 25 years of follow-up is about 30%. However, when the competing causes of death are taken into account, the actual rate of progression is only 11%. The predictors of malignant transformation are the plasma cell mass (M-protein size and/or proportion of plasma cell in the bone marrow), IgA isotype, serum free light-chain ratio and 'evolving' type and ratio between phenotypically aberrant and normal bone marrow plasma cells. It is recommended to follow these patients, particularly those with high risk of progression, annually to detect MM before complications, such as renal failure or extensive skeletal, involvement occur. Leukemia ConceptThe term monoclonal gammopathy of undetermined significance (MGUS) indicates the presence of a monoclonal protein (M-protein) in individuals with no features of multiple myeloma (MM), Waldenströ m's macroglobulinemia, primary amyloidosis or other related disorders. 1 Patients with MGUS have a serum M-protein size lower than 3 g per 100 ml, and proportion of bone marrow plasma cells of less than 10%, with no clinical manifestations related to their monoclonal gammopathy (Table 1). 1,2 MGUS was initially considered to be a benign condition and was frequently named 'benign' or 'idiopathic' monoclonal gammopathy. 3,4 However, from the time of the pioneer observations in the Mayo Clinic (Rochester, MN, USA) series, this disorder could no longer be considered as 'benign' as a number of patients ultimately develop a malignant monoclonal gammopathy. 1,[5][6][7][8] For this reason, Dr Robert Kyle coined the term 'monoclonal gammopathy of undetermined significance'. 1,5 Considering that MGUS is usually an unexpected finding in a routine medical survey, or in the study of an unrelated disorder, not surprisingly, this condition is usually first seen by physicians working in many different fields of medical practice. In consequence, it is crucial to know the significance of the finding: whether it will require further investigation and whether it will remain stable or, by the contrary, will evolve into a symptomatic monoclonal gammopathy requiring therapeutic intervention. 9 EpidemiologyPrior studies based on Caucasians showed that the prevalence of MGUS increases with age. For many years, it was considered that the prevalence of MGUS was 1 and 3 % in persons older than 50 and 70 years, respectively. 10-14 However, in a recent study performed on residents of Olms...

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Section: Mechanisms Of Progressionmentioning

confidence: 50%

Pathogenesis and progression of monoclonal gammopathy of undetermined significance

et al. 2008

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“…Plasma cells in the bone marrow microenvironment secrete cytokines, such as tumor necrosis factor-alpha (TNF-a) (Hideshima et al, 2001c), transforming growth factor-beta (TGF-b) , VEGF (Dankbar et al, 2000), FGF-2 , HGF-SF (Borset et al, 1996a) , Ang-1 (Giuliani et al, 2002) and matrix metalloproteinases (MMPs) (Barilleé t al., 1997;Vacca et al, 1999). Moreover, binding of plasma cells to BMSC triggers transcription and secretion by the latter of cytokines, such as IL-6 (Dankbar et al, 2000), IGF-1 (Ferlin et al, 2000) and VEGF (Gupta et al, 2001) and CXCL12/stromal cellderived factor-1a (SDF-1a) (Pellegrino et al, 2005), that mediate cell growth (IL-6, IGF-1, VEGF), survival (IL-6, IGF-1), drug resistance (IL-6, IGF-1, VEGF), migration (IGF-1, VEGF, MMPs, SDF-1a) and angiogenesis (VEGF) in the bone marrow.…”

Section: Multiple Myeloma Microenvironmentmentioning

confidence: 99%

“…Tumor necrosis factor-alpha secreted by plasma cells induces NF-kappa B-dependent upregulation of adhesion molecules on both MM and BMSC (CD49d, CD54) (Hideshima et al, 2001c), thereby increasing the binding of MM to BMSC with associated cell adhesion mediated-drug resistance and induction of IL-6, IGF-1 and VEGF secretion by BMSC Hideshima et al, 2001aHideshima et al, , 2002b.…”

Section: Vascular Endothelial Growth Factormentioning

confidence: 99%

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

2006

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Tumor microenvironment is essential for tumor cell proliferation, angiogenesis, invasion and metastasis through its provision of survival signals, secretion of growth and pro-angiogenic factors, and direct adhesion molecule interactions. This review examines its importance in the induction of an angiogenic response in multiple myeloma (MM). The encouraging results of preclinical and clinical trials in which MM has been treated by targeting the tumor microenvironment are also discussed.

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“…NF-κB promotes growth, survival, and drug resistance in multiple myeloma cells (6). Moreover, NF-κB upregulates adhesion molecules and promotes cytokine secretion in both multiple myeloma cells and bone marrow stromal cells, thus contributing to cell adhesion-mediated drug resistance (7)(8)(9). Accordingly, inhibitors of IKKβ inhibit multiple myeloma cell growth (10)(11)(12) and first NF-κB inhibitors have been shown to induce apoptosis in multiple myeloma cells (6,13).…”

Section: Introductionmentioning

confidence: 99%

The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

Meinel

Mandl-Weber

Baumann

et al. 2010

Molecular Cancer Therapeutics

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Evidence is increasing that aberrant NF-κB activation is crucial for multiple myeloma pathophysiology and a promising target for new antimyeloma therapies. In this study, we assessed the in vitro antimyeloma activity of the novel NF-κB inhibitor V1810. Pharmacokinetics and toxicity were studied in vivo. In mice, V1810 plasma concentrations of 10 μmol/L can be reached without relevant toxicity. At this concentration, V1810 potently induces apoptosis in all four multiple myeloma cell lines assessed (IC 50 = 5-12 μmol/L) as well as in primary multiple myeloma cells (IC 50 = 5-40 μmol/L). Apoptosis induced by V1810 is associated with proteasomeindependent inhibition of NF-κB signaling (41% relative reduction), downregulation of Mcl-1, and caspase 3 cleavage. In OPM2, U266, and RPMI-8226 cells, induction of apoptosis is accompanied by cell cycle arrest. Western blots revealed downregulation of Cdk4 as well as cyclin D1 (U266) or cyclin D2 (OPM2, NCI-H929, RPMI-8226), but not cyclin D3. Consistently, retinoblastoma protein was found to be hypophosphorylated. Furthermore, V1810 reverses NF-κB activation induced by the genotoxic drugs melphalan and doxorubicin. V1810 and melphalan synergistically decrease multiple myeloma cell viability. Taken together, the novel, proteasome-independent NF-κB inhibitor V1810 induces apoptosis and cell cycle arrest in multiple myeloma cells at a concentration range that can be achieved in vivo. Moreover, V1810 reverses NF-κB activation by alkylating drugs and overcomes NF-κB-mediated resistance to melphalan. Mol Cancer Ther; 9(2); 300-10. ©2010 AACR.

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The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications

Cited by 362 publications

References 45 publications

Pathogenesis and progression of monoclonal gammopathy of undetermined significance

Pathogenesis and progression of monoclonal gammopathy of undetermined significance

Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma

The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

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