Contrast in cytokine expression between patients with monoclonal gammopathy of undetermined significance or multiple myeloma

Donovan, KA; Lacy, M. Q.; Kline, MP; Ahmann, GJ; Heimbach, J.; Ra, Kyle; Lust, JA

doi:10.1038/sj.leu.2400873

Cited by 36 publications

(26 citation statements)

References 18 publications

(29 reference statements)

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“…These findings proved that the serum level of IL-6 is a significant prognostic marker in multiple myeloma patients. 7 In accordance with this hypothesis, a relation between the duration of overall survival and the serum level of IL-6 was investigated. Results coming from some clinical studies demonstrated that survival times differed significantly between patients whose IL-6 levels were Ͻ 7 pg/mL at the time of diagnosis and those with IL-6 concentrations of Ն 7pg/mL.…”

Section: Significance Of Il-6 and The Network Of Several Cytokines Inmentioning

confidence: 84%

“…6 Results from other clinical trials have confirmed these data but they also have reported that high IL-6 serum levels were found in patients with acute non-lymphoblastic leukemia as well as in those with multiple myeloma. 7 These data confer an additional diagnostic value to IL-6 that may allow for the distinction of multiple myeloma from MGUS. Moreover, the high expression of IL-6 mRNA on cellular populations in MGUS patients could predict those patients whose disease eventually will progress to multiple myeloma.…”

Section: Significance Of Il-6 and The Network Of Several Cytokines Inmentioning

confidence: 99%

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A review of the cytokine network in multiple myeloma

Lauta

2003

Cancer

196

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Because many studies have focused on growth factors in multiple myeloma, the study of the cytokine network appears to be useful for this purpose. Interleukin-6 (IL-6) and IL-2 with their soluble receptors (IL-3, IL-4, IL-10, and IL-11) have been examined. Plasma cells may produce IL-6 by an autocrine mechanism whereas a paracrine mechanism is believed to be involved in the production of IL-6 by bone However, the concomitant evaluation of all immunologic parameters could be more useful than the value of a single IL. Serum levels of IL-6, sIL-6R, sIL-2R, and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells, are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels are believed to be correlated with the duration of disease-free survival because a high serum level at the time of diagnosis is believed to be correlated with a short duration of survival. However, some laboratory parameters may express the same prognostic value as high ␤ 2 microglobulin and lactate dehydrogenase (LDH) serum levels together with a high plasma cell labeling index are correlated with disease activity.Furthermore, if the evaluation is performed at the time of diagnosis, high values of these parameters are correlated with a short disease-free survival. A correlation between laboratory parameters and the serum level of several cytokines was demonstrated. Hence, the real advantage of the prognostic evaluation of cytokines is reserved for patients who do not exhibit uniform results with regard to ␤ 2 microglobulin and LDH serum levels, or, better, for borderline cases. With regard to the differential diagnosis, all immunologic parameters should be evaluated concomitantly rather than separately to confer a real prognostic value to results. Furthermore, a particular relation was found between a high sIL-6R serum level and a poor response to chemotherapy, therefore suggesting the possibility of identifying in advance a subset of patients with a high risk of treatment failure, as has already been demonstrated in other hematologic malignancies.Finally, the majority of studies indicate that interferons are used mainly in the immunotherapy for multiple myeloma, whereas many clinical trials should still be required for the evaluation of the effectiveness of anti-I-L6 antibodies or antiidiotypic vaccines in reference to the eligible patients for these particular therapies.

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Section: Significance Of Il-6 and The Network Of Several Cytokines Inmentioning

confidence: 84%

Section: Significance Of Il-6 and The Network Of Several Cytokines Inmentioning

confidence: 99%

A review of the cytokine network in multiple myeloma

Lauta

2003

Cancer

196

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“…(29,30) and TGF-h (31). These molecules induce hepcidin expression in vitro and may be expressed at high level in myeloma patients (32,33).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Hepcidin in the Anemia of Multiple Myeloma

Sharma

Nemeth

Chen

et al. 2008

Clinical Cancer Research

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Purpose: Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma. Experimental Design: Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-a, and IL-1h were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay. Results: Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect. Conclusions: These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.

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“…[5][6][7] Partly by producing interleukin-1 (IL-1), MM cells induce bone marrow stromal cells to synthesize IL-6, a major cytokine in MM biology. [8][9][10][11] However, purified MM cells cannot be rescued, even by IL-6, and require the presence of stromal cells for in vitro survival. [12][13][14][15] Thus, in the chronic phase of the disease, some molecules produced by stromal cells are critical, combined with IL-6, to promoting MM cell survival and proliferation.…”

mentioning

confidence: 99%

Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays

Vos

Couderc

Tarte

et al. 2001

Blood

143

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In multiple myeloma (MM), the growth of primary plasma cells depends not only on interleukin-6 (IL-6), but also on additional unidentified signals delivered by the bone marrow environment. Using Atlas complementary DNA (cDNA) arrays comprising 268 genes coding for intercellular signaling molecules, this study identified genes that are overexpressed in myeloma cells compared to autologous B-lymphoblastoid cell lines. These genes encode the oncogenic Tyro3 tyrosine kinase receptor, the heparin-binding epidermal growth factor-like growth factor (HB-EGF) that is an epithelial autocrine tumor growth factor, the thrombin receptor (TR) that is linked to HB-EGF and syndecan-1 processing and to cell invasion, chemokine receptors CCR1 and CCR2, the Wnt pathway actor Frizzled-related protein (FRZB), and the Notch receptor ligand Jagged 2. These data, obtained with the Atlas cDNA array, were confirmed by reverse transcriptase-polymerase chain reaction or protein analysis or both. Furthermore, Tyro3, HB-EGF, TR, and FRZB gene expression was documented in purified primary malignant plasma cells from patients with plasma cell leukemia or MM. HB-EGF and FRZB were poorly expressed in purified polyclonal plasma cells. Finally, HB-EGF was proved to be an essential autocrine growth factor for the XG-1 myeloma cells. This study shows the po- IntroductionTumor development involves multiple mechanisms that lead to an increase in the survival of tumor cells and a deregulation of the cell cycle. Specifically, cell-to-cell growth signaling is likely to operate between tumor cells and their neighboring stromal cells. 1 In multiple myeloma (MM), the tight interactions between malignant plasma cells and their medullar environment exemplify this oncogenic process. As recently reported, myeloma cells produce the angiogenic growth factors, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), which may promote the neovascularization of the bone marrow observed as the disease activity increases. [2][3][4] Malignant plasma cells express adhesion molecules such as VLA4 and CD44, whose interactions with stromal cells and the extracellular matrix sustain MM cell survival. [5][6][7] Partly by producing interleukin-1 (IL-1), MM cells induce bone marrow stromal cells to synthesize IL-6, a major cytokine in MM biology. [8][9][10][11] However, purified MM cells cannot be rescued, even by IL-6, and require the presence of stromal cells for in vitro survival. [12][13][14][15] Thus, in the chronic phase of the disease, some molecules produced by stromal cells are critical, combined with IL-6, to promoting MM cell survival and proliferation. Growth factors able to bind heparan sulfate, such as FGFs, could be candidate molecules. Indeed, translocations involving the FGF receptor 3 are found in MM cells from patients with active disease and can confer an increase in the response of MM cells to IL-6 in vitro. 16,17 Moreover, MM cells are the only cells in the bone marrow that express syndecan-1, a heparan sulfate proteoglycan that i...

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Contrast in cytokine expression between patients with monoclonal gammopathy of undetermined significance or multiple myeloma

Cited by 36 publications

References 18 publications

A review of the cytokine network in multiple myeloma

A review of the cytokine network in multiple myeloma

Involvement of Hepcidin in the Anemia of Multiple Myeloma

Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays

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