Long‐term bone marrow cultured stromal cells regulate myeloma tumour growth <i>in vitro</i>: studies with primary tumour cells and LTBMC‐dependent cell lines

Bloem, Andries C.; Lamme, Tanja; Smet, Martin De; Kok, Henriette; Vooijs, Wim C.; Wijdenes, John; Boom, Saskia E.; Lokhorst, Henk M.

doi:10.1046/j.1365-2141.1998.00517.x

Cited by 29 publications

(23 citation statements)

References 48 publications

(66 reference statements)

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“…This is especially relevant in the light of recent observations that soluble IL-6R may be a critical factor delivered by bone marrow stromal cells to primary myeloma cells. 21,22 Moreover, other IL-6-related cytokines can substitute for IL-6 to sustain the growth of IL-6-dependent HMCL. 14 These cytokines may therefore play a role in the pathobiology of MM.…”

Section: Discussionmentioning

confidence: 99%

“…Two recent reports have described the obtaining of myeloma cell lines whose growth was supported by bone marrow stromal cells. 21,22 The stromal cell supernatants could be replaced by a combination of IL-6 and sIL-6R but not by IL-6 alone. These data suggest that membrane IL-6R expression on myeloma cells might be a limiting factor for IL-6-mediated gp130 signaling.…”

Section: Introductionmentioning

confidence: 99%

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Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Vos

Rebouissou³

et al. 2000

Leukemia

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We have previously reported obtaining two monoclonal antibodies (mAb) against the human gp130 interleukin-6 (IL-6) transducer which made possible the dimerization of gp130 and the activation of several IL-6-driven functions when used together. We report here that these mAb induce gp130-mediated signaling in human myeloma cells and support the survival and the long-term growth of five IL-6-dependent human myeloma cell lines. Their agonist activity is not affected by neutralizing antibodies to IL-6 or IL-6R. These mAb induce a transient proliferation of primary myeloma cells from most patients with multiple myeloma. Again, IL-6 inhibitors do not affect this agonist activity. By using highly purified primary myeloma cells, we found that these anti-gp130 mAb supported the long-term survival of primary myeloma cells from five patients with primary plasma cell leukemia but failed to induce their long-term growth. For patients with fulminant disease and secondary extramedullary proliferation, the antibodies supported a long-term survival and growth, and anti-gp130 mAbdependent cell lines were obtained. For patients with medullary involvement only, a co-stimulatory signal is necessary, together with gp130 activation, to trigger cell survival and cycling. Leukemia (2000) 14, 188-197.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Vos

Rebouissou³

et al. 2000

Leukemia

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“…Plasma cell lines UM-1 and UM-3 were obtained after prolonged in vitro culture of bone marrow aspirates of myeloma patients and have been described before. 30 The plasma cell line UM-6 was obtained under identical conditions as described above. UM-6 cells express high levels of the plasma cell-associated antigens, CD38, CD138 and cytoplasmic lgAkappa, as determined by flow cytometric analysis and immunofluorescence microscopy, respectively.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells

et al. 2002

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Lovastatin is an irreversible inhibitor of HMG-CoA reductase and blocks the production of mevalonate, a critical compound in the production of cholesterol and isoprenoids. Isoprenylation of target proteins, like the GTP-binding protein Ras, is essential for their membrane localization and subsequent participation in intracellular signaling cascades. Lovastatin effectively decreased the viability of plasma cells from cell lines (n = 10) and myeloma patients' samples (n = 8) in a dose-and time-dependent way. Importantly, co-incubation of lovastatin with dexamethasone had a synergistic effect in inducing plasma cell cytotoxity. This effect was not the consequence of a change in the protein expression levels of Bcl-2 or Bax induced by lovastatin. The decrease in plasma cell viability was the result of induction of apoptosis and inhibition of proliferation. Mevalonate effectively reversed the cytotoxic and cytostatic effects of lovastatin in plasma cells. The cytotoxic activity of lovastatin was higher in Pgp expressing cell lines, but did not correlate with the multidrug resistance (MDR)-related proteins LRP, Bcl-2 and Bax. Lovastatin treatment resulted in a shift of Ras localization from the membrane to the cytosol that was reversed by mevalonate. The data presented in this paper warrant study of lovastatin alone or in combination with therapeutic drugs, in the treatment of myeloma patients.

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“…1-5 days). 14 The bone marrow biopsy was performed after 2 months from the last cycle of therapy, in the DAV group (median; range 1-16) and after 3 months (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) in the MP group. Patients in the MP group have been treated with 12 cycles (4-26) while in the DAV group patients received six therapy cycles (4)(5)(6)(7)(8).…”

Section: Patientsmentioning

confidence: 99%

“…We have also examined in this system the effect of the addition of monoclonal antibody anti-IL6, which is known to prolong survival and proliferation of MPC in vitro and also to promote angiogenesis. 10,11 Patients and methods…”

Section: Introductionmentioning

confidence: 99%

Angiogenesis in multiple myeloma: correlation between in vitro endothelial colonies growth (CFU-En) and clinical–biological features

et al. 2001

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Mouse models and studies performed on fixed bone marrow (BM) specimens obtained from patients with multiple myeloma (MM) suggest that plasma cell growth is dependent on endothelial cell (EC) proliferation within the BM microenvironment. In order to assess whether EC overgrowth in MM reflects a spontaneous in vitro angiogenesis, BM mononucleated cells from 13 untreated (UT) MM, 20 treated (11 with melphalan and nine with DAV schedule) MM, eight patients with monoclonal gammopathy of uncertain significance (MGUS) and eight controls were seeded in an unselective medium to assess EC proliferation. Furthermore, the influence of IL6 on the EC growth was investigated. Endothelial colonies (CFU-En) appeared as small clusters, formed by at least 100 slightly elongated and sometimes bi-nucleated cells expressing factor VIII, CD31 and CD105 (endoglin). The CFU-En mean number/10 6 BM mononucleated cells in untreated MM samples (2.07 s.d. ± 1.3) was significantly higher than in normal BM (0.28 ± 0.48), while no difference was seen between normal BM and MGUS (0.28 ± 0.54). Interestingly, the mean number of CFU-En in the DAV group (1.88 ± 1.6) did not differ from the UT, while it was found to be lower in the melphalan group (0.31 ± 0.63). The addition of anti-IL6 monoclonal antibody induced a reduction of both the plasma cells in the supernatant and the CFU-En number. This study describes a rapid and feasible assay providing support for the association between EC and plasma cells further suggesting that the in vitro angiogenesis process may parallel that observed in vivo. Leukemia (2001) 15, 171-176.

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Long‐term bone marrow cultured stromal cells regulate myeloma tumour growth in vitro: studies with primary tumour cells and LTBMC‐dependent cell lines

Cited by 29 publications

References 48 publications

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

Agonist anti-gp130 transducer monoclonal antibodies are human myeloma cell survival and growth factors

The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells

Angiogenesis in multiple myeloma: correlation between in vitro endothelial colonies growth (CFU-En) and clinical–biological features

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