Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The addition of macrophage feeder cells or conditioned medium has been shown to increase the yield of murine hybridomas obtained after the fusion of myeloma cells and activated B lymphocytes. It has been shown recently that the conditioned medium contains a growth factor (HGF) active on newly formed hybridomas and that the human HGF is similar to B cell stimulatory factor 2 which can induce the synthesis of antibodies in transformed B cells. We have compared in several fusion experiments the stimulatory effects of HGF both on the yield of hybridomas and on the number of antibody-secreting hybridomas. The results obtained clearly showed that while the stimulatory effect of HGF on the yield of growth-positive wells was variable and sometimes barely detectable, the proportion of growth-positive wells containing monoclonal antibodies was consistently much higher in the HGF-containing cultures. These results suggest that the majority of the antibody-secreting newly formed hybridomas are sensitive to HGF and indicate that HGF is a very useful culture supplement for the generation of a high number of antibody-producing hybridomas even if it may not increase significantly the yield of viable hybridomas.
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PMID:Increased proportion of B cell hybridomas secreting monoclonal antibodies of desired specificity in cultures containing macrophage-derived hybridoma growth factor (IL-6). 278 46

It has been shown recently that monocyte-macrophage cells produce a growth factor (HGF) active on newly formed B cell hybridomas. We have studied the effect of HGF on the proliferation of an HGF-sensitive clone of B cell hybridoma. Results obtained showed that the murine P388D1 cell-derived HGF has a m.w. of 29,000 and an isoelectric point (pI) of 6.2 whereas the human monocyte-derived HGF has a m.w. of 34,000 and a pI of 4.9. The HGF activity was not mediated by interleukin 1 because the two activities could be completely separated by gel filtration. Results obtained in in vivo experiments showed that HGF-sensitive cells are tumorigenic in mice. The finding that the HGF biochemical parameters (m.w. and pI) are similar to the ones of a recently described plasmacytoma growth factor suggests that HGF and the plasmacytoma growth factor are similar and that the HGF sensitivity of SP 2/O myeloma cells is reactivated after fusion with normal B lymphocytes.
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PMID:Role of the macrophage-derived hybridoma growth factor in the in vitro and in vivo proliferation of newly formed B cell hybridomas. 349 90

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.
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PMID:Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. 1116 14

Supernatants from short-term culture of peripheral blood and bone marrow mononuclear cells obtained from 22 multiple myeloma patients were used to measure the concentration of TNF-alpha, HGF, IL-6 and its soluble receptor (sIL-6R), VEGF and bFGF. Cells were cultured with or without thalidomide (THAL). We observed statistically significant decrease in TNF-alpha, HGF, IL-6, sIL-6R in supernatants from THAL cultures compared to cells cultured without THAL. Flow cytometry technique was applied to study the Bcl2 expression on CD 4, CD 8 and CD 138 positive cells. The statistically significant decrease in Bcl2 expression on myeloma cells (CD 138+) was observed both in PB and BM cultures. THAL could inhibit the plasma cell growth both by diminishing proangiogenic cytokines production and enhancing myeloma cell apoptosis.
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PMID:Influence of thalidomide on Bcl2 expression and proangiogenic cytokine levels in short-term culture of peripheral blood and bone marrow mononuclear cells of multiple myeloma patients. 1198 51

Thalidomide (THAL) is currently used as a novel drug in patients with chemotherapy resistant or relapsed multiple myeloma. THAL antitumor activity seems to be very complex, however the precise mechanisms of its action are still not fully understood. The aim of this study was to assess some of possible mechanisms of THAL action both in in vivo analysis of immune cells phenotype and in in vitro cultures with THAL. The study involved 30 patients with relapsed or chemotherapy refractory multiple myeloma who were qualified to THAL treatment. We assessed immunophenotype of malignant plasma cells and T lymphocytes in both peripheral blood (PB) and bone marrow (BM) samples taken before and after 4 and 8 weeks of THAL treatment. Before therapy cytokine secretion (VEGF, HGF, bFGF, TNF, IL-6 an sIL-6R) and Bcl-2 expression in PB and BM cell cultures with THAL were analyzed. We used flow cytometry technique and ELISA method. The clinical response to therapy was assessed after 4 and 8 weeks of treatment. We also investigated microvessel density (MVD) in bone marrow samples before the THAL treatment and after 6 months of therapy in the group of responding patients. In cell cultures with THAL we detected statistically significant lowering of analyzed cytokines concentration and the decrease in Bcl-2 expression by malignant plasma cells in BM and CD8(+) T lymphocytes in BM and PB. In the group of patients responding to therapy we observed the decrease in the number of myeloma cells and significant increase of CD4(+) and CD8(+) cells in both PB and BM samples. There was statistically significant increase of CD3(+)/CD69(+) cells in the course of therapy, while the percentage of CD3+/HLA-DR(+) cells was significantly lower after 8 weeks of therapy. We also detected lowering of MVD after THAL therapy in responders group. The obtained results demonstrate that THAL efficacy in MM is multidirected and included such mechanisms like down-regulation of proangiogenic cytokines, that could lead to lowering of MVD, induction of apoptosis and influence on malignant cells and T lymphocytes immunophenotype.
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PMID:The influence of thalidomide therapy on cytokine secretion, immunophenotype, BCL-2 expression and microvessel density in patients with resistant or relapsed multiple myeloma. 1580 Jul 17

In multiple myeloma, a large number of growth factors (IL-6, IGF-1, FGF, HGF and HB-EGF) are involved in promoting myeloma cell growth. In the present study, a serum-free, cytokine-free, collagen-based assay, which does not allow the generation of spontaneous myeloma colonies, was used to identify the clonogenic growth factors for fourteen myeloma cell lines. IL-6 is the only clonogenic factor able to stimulate both CD45+ and CD45- myeloma cell lines, generating myeloma colonies from 10 out of 14 myeloma cell lines. Using a pharmacological Erk inhibitor, we show that the Erk/MAPK pathway is involved in IL-6-induced clonogenicity of CD45+, but not CD45- myeloma cell lines. In contrast to IL-6, the other growth factors (IGF-1, FGF, HGF and HB-EGF) stimulate only some myeloma cell lines, but always CD45-, and less effectively than IL-6. Among them, IGF-1 is the most potent, generating myeloma colonies from five out of eight CD45- myeloma cell lines. Finally, the capacity of IGF-1 and FGF to stimulate the clonogenicity of CD45- myeloma cells correlates with their ability to stimulate the Erk/MAPK pathway. We conclude that CD45 expression plays a crucial role in determining signaling and proliferation of human myeloma cell responses to IL-6, IGF-1 and other growth factors. The poor outcome of CD45- myeloma patients could be related to the capacity of CD45-myeloma cells to take advantage of multiple growth factors.
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PMID:Crucial role of phosphatase CD45 in determining signaling and proliferation of human myeloma cells. 1782 79

Adhesion of multiple myeloma (MM) cells in the bone marrow (BM) is important for the growth and survival of the myeloma cells. Very late antigen-4 (VLA-4) is one of the main adhesion receptors that mediate MM cell binding to fibronectin (FN). In this study we have examined the effect of divalent cations on adhesion of MM cells to FN, and compared this type of adhesion with the adhesion induced by the cytokines HGF, IGF-1 and SDF-1alpha. Mn(2+) induced adhesion in all cell lines tested. Cytokine- and Mn(2+)-induced VLA-4-mediated adhesion were different in many respects, including binding specificity, adhesion kinetics and the activation state of VLA-4. To study a potential role of divalent cations in vivo, we measured the concentrations of divalent cations in BM plasma from 14 MM patients. We also found that Mn(2+)-mediated adhesion to FN activated the MAPK pathway, indicating that the interaction of MM-cells with FN mediated by Mn(2+) could play a critical role for growth and proliferation. In conclusion, this study shows a potential important role of divalent cations in MM cell biology and supports earlier studies pointing to activated VLA-4 as a key for homing of MM cells to the BM.
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PMID:Mn2+ regulates myeloma cell adhesion differently than the proadhesive cytokines HGF, IGF-1, and SDF-1alpha. 1877 52

A plethora of myeloma growth factors (MGFs) has been identified, but their relative importance and cooperation have not been determined. We investigated 5 MGFs (interleukin-6 [IL-6], insulin-like growth factor type 1 [IGF-1], hepatocyte growth factor [HGF], HB-epidermal growth factor [HB-EGF], and a proliferation-inducing ligand [APRIL]) in serum-free cultures of human myeloma cell lines (HMCLs). In CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival whereas CD45(+) HMCLs could not survive without addition of MGFs, mainly IGF-1 and IL-6. IGF-1 was the major one: its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF, or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression without t(4;14) can also have a poor prognosis. Thus, IGF-1-targeted therapy, eventually in combination with anti-IL-6 therapy, could be promising in a subset of patients with MMCs expressing IGF-1R.
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PMID:The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. 1922 10

Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.
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PMID:Induction of angiogenesis by normal and malignant plasma cells. 1929 35

We examined cytokine production by bone marrow stromal cells (BMSCs) of patients with multiple myeloma (MM) in response to contact with myeloma RPMI8226 cells in standard 2-dimensional (2D) cultures and in 3-dimensional (3D) cultures on a gelatine sponge scaffold. It was detected that BMSCs in the 3D cultures produced more IL-11 and HGF and less IL-10 than in the 2D cultures. Moreover, RPMI8226 cells after contact with BMSCs in 3D cultures produced more sIL-6R than in the classic 2D cultures. We concluded that 3D cultures of BMSCs with myeloma cells offered a promising model for in vitro examination of interactions between myeloma cells and the bone marrow stroma and for examination of potent antimyeloma agents.
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PMID:A comparison of cytokine production in 2-dimensional and 3-dimensional cultures of bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells. 1941 41


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