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)

Interleukin-6 (IL-6) is essential for the proliferation of myeloma cells, and IL-6 is considered to be produced from not only myeloma cells themselves but also microenvironments including stromal cells. To clarify which subpopulation of myeloma cells can produce IL-6, we examined IL-6 mRNA expression in immature and mature myeloma cells and normal plasma cells by RT-PCR. IL-6 mRNA expression was found in all (10/10) specimens of sorted VLA-5-MPC-1- immature myeloma cells and 27% (3/11) of VLA-5-MPC-1+ myeloma cells. On the contrary, no IL-6 mRNA was expressed in VLA-5+MPC-1+ mature myeloma cells (0/4) and CD19+CD56- normal plasma cells (0/5). IL-6R gene expression was detected in all normal and malignant plasma cells without exception. Therefore, these findings suggest that IL-6 production is preferentially restricted in immature not mature myeloma cells, and this may explain why immature myeloma cells show greater proliferative activity.
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PMID:Interleukin-6 gene expression is preferentially restricted in VLA-5-MPC-1- immature but not in VLA-5+MPC-1+ mature myeloma cells. 893 35

The neoplastic plasma cells of multiple myeloma differ from normal plasma cells and other B-cell malignancies by an almost exclusive homing to the bone marrow microenvironment which clearly provides the appropriate support, both physical and cytokine, to mediate clonal proliferation and terminal differentiation. Cellular adhesion molecules are involved in the homing of malignant plasma cells to the bone marrow, the production of growth factors and the recirculation of these tumour cells in the advanced stages of disease. Neoplastic plasma cells express H-CAM (CD44), VLA-4 (CD49d/CD29), ICAM-1 (CD54), N-CAM (CD56) and LFA-3 (CD58). In addition VLA-5 (CD49e/CD29) expression seems to be related to cells with less proliferative potential and more potential for paraprotein production. In addition there are fundamental changes in the bone marrow stroma of patients with multiple myeloma including altered composition of the extracellular matrix, increased growth capability of the cellular elements and increased synthesis of interleukin-6 and interleukin-3, which are features postulated to localise and promote growth of the circulating neoplastic progenitors in the bone marrow. However, the evidence to date does not fully explain the inter-relationship of the clonal B cells and the bone marrow stroma in patients with myeloma, including factors which trigger and facilitate the extravasation and recirculation of neoplastic plasma cells as seen in advanced disease.
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PMID:The role of adhesion molecules in multiple myeloma. 898 Jun 13

Long-term bone marrow cultures (LTBMC) were established from marrow samples obtained from 6 myeloma patients and 5 healthy donors and were examined by in situ immunogold-silver staining. During the culture period, the established stroma in myeloma LTBMC revealed a lower level of confluency compared to the normal LTBMC. In addition, an increasing proportion of macrophages and osteoclasts was observed in the myeloma stroma throughout the culture period. Moreover, plasma cells were detectable by wk 8, mostly organized in small clusters. They strongly expressed VLA-4 (6/6), H-CAM (6/6), ICAM-1 (6/6) and N-CAM (3/6). In most cases, a weak expression of the other members of beta 1-integrins was observed. The expression of beta 2-integrins was always absent. Stromal fibroblasts were found to be weakly positive for VLA-2, VLA-3 and VLA-5 and showed strong expression of VCAM-1, H-CAM and ICAM-1. N-CAM expression could not be detected. By comparing the adhesion molecule profile of the stromal cells in myeloma cultures with normal bone marrow (BM) cultures, no particular defects could be observed. The stroma displayed most of the potential ligands which could interact with adhesion molecules detected on the myeloma cells. Among these ligands we could find fibronectin and VCAM-1 for VLA-4, collagen I for VLA-2 and VLA-3 and laminin for VLA-2, 3 and 6. Four myeloma cell lines, i.e. OPM-1, U266, RPMI 8226 and JJN3, with a representative phenotype, were used to study the adhesive interactions of myeloma cells with the BM microenvironment. All the myeloma cell lines bound strongly to the marrow cell layers and also showed a high binding to purified fibronectin (FN). However, the adhesion of the cell lines to intact stroma could not be significantly inhibited by anti-FN receptors antibodies. Nor could it be prevented when the latter were combined with anti-H-CAM, V-CAM and ICAM-1 antibodies, as tested in the JJN3 cell line. This implies that other unknown mechanisms contribute to the myeloma cell binding.
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PMID:Adhesive interactions between tumour cells and bone marrow stromal elements in human multiple myeloma. 900 75

The purpose of this study was to optimize the flow cytometric determination of circulating normal and malignant plasma cells (PC). We investigated peripheral blood (PB) samples of 65 patients with multiple myeloma or monoclonal gammopathy of unknown significance and 47 control subjects using CD38, CD45, B-B4, CD56, VLA-4, VLA-5 and CD19 monoclonal antibodies (MoAbs). Mono- or polyclonality was determined by staining of intracellular kappa and lambda light chains. Two subpopulations of PBPC were distinguished by differential expression of CD45. CD45 positive (CD45+) PC showed a more immature morphology and were detected in all groups. They were polyclonal in the control subjects and either poly- or monoclonal in the myeloma patients. In contrast, CD45 negative (CD45-) PBPC only occurred in myeloma patients and were consistently monoclonal, their presence being significantly associated with high disease activity (P < 0.001). Although detection of CD45- PBPC using CD38 or B-B4 MoAbs lead to similar results. CD45+ PBPC often were recognized to a lesser extent by B-B4 than by CD38 MoAbs. In conclusion, normal and malignant circulating PC can reliably be identified using CD38 and CD45 MoAbs. CD45 expression separates PBPC into two subsets of which the CD45- one only occurs in myeloma patients.
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PMID:Two subsets of peripheral blood plasma cells defined by differential expression of CD45 antigen. 913 42

The aim of this study was to evaluate the tissue infiltration and phenotypic adhesion profile of 5T2 multiple myeloma (MM) and 5T33 MM cells and to correlate it with that observed in human disease. For each line, 30 mice were intravenously inoculated with myeloma cells and at a clear-cut demonstrable serum paraprotein concentration; mice were sacrificed and a number of organs removed. The haematoxylin-eosin stainings on paraffin sections were complemented with immunohistochemistry using monoclonal antibodies developed against the specific MM idiotype. When analysed over time, 5T2 MM cells could be observed in bone marrow samples from week 9 after transfer of the cells. For the 5T33 MM, a simultaneous infiltration was observed in bone marrow, spleen and liver 2 weeks after inoculation. Osteolytic lesions consistently developed in the 5T2 MM, but this was not consistent for 5T33 MM. PCNA staining showed a higher proliferative index for the 5T33 MM cells. The expression of adhesion molecules was analysed by immunohistochemistry on cytosmears: both 5T2 MM and 5T33 MM cells were LFA-1, CD44, VLA-4 and VLA-5 positive. We conclude that both lines have a phenotypic adhesion profile analogous to that of human MM cells. As the 5T2 MM cells are less aggressive than the 5T33 MM cells, their organ distribution is more restricted to the bone marrow and osteolytic lesions are consistently present, the former cell line induces myeloma development similar to the human disease.
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PMID:Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. 927 21

Myeloma cells consist of immature, intermediate and mature cells with respect to expression of VLA-5 (CD49e) and MPC-1 adhesion molecules. VLA-5(-)MPC-1(-) immature myeloma cells respond to interleukin 6 (IL-6) to proliferate in vitro. but VLA-5+MPC-1+ mature myeloma cells have almost no proliferative activity with higher secretory activity of M-protein in vitro. In order to further clarify the biological differences between these immature and mature myeloma cells, we examined survival of these cells with or without IL-6 in vitro, and investigated the underlying mechanism of the proliferative or non-proliferative character of these cells by examining expression of cell cycle regulators such as cyclin D1 and inhibitors for cyclin-dependent kinase (Cdk), p16INK4A, p21CIP1 and p27KIP1 by RT-PCR and immunohistochemistry. In vitro survival of these myeloma cells was examined by flow cytometric quantification of fluorescein diacetate (FDA) and propidium iodide (PI) staining. Immature myeloma cells rapidly entered apoptosis without IL-6, but mature myeloma cells could survive without IL-6 as well as normal mature plasma cells. Immature myeloma cells as well as myeloma cell lines expressed cyclin D1 mRNA and protein, but not any Cdk inhibitors. On the other hand, mature myeloma cells did not express cyclin D1 but expressed p16, not p21 or p27, as well as normal mature plasma cells. Therefore these results show that immature myeloma cells constitutively express cyclin D1 and can proliferate, and mature myeloma cells as well as normal mature plasma cells preferentially express p16 and can survive for a long time without proliferation.
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PMID:Cyclin D1 and p16INK4A are preferentially expressed in immature and mature myeloma cells, respectively. 935 13

beta 1 Integrins are considered to be essential for the differentiation of bone-marrow B cells through an interaction with fibronectin-expressed bone-marrow stromal cells. The expression of very late antigens-4 (VLA-4) and -5 (VLA-5) by CD38bright bone-marrow cells in patients with multiple myeloma was measured by flow cytometry using specific monoclonal antibodies. The percentage of CD38bright bone-marrow cells appeared to correlated with that of bone-marrow plasma cells as judged by examination of bone-marrow smears (r = 0.911, P < 0.0001). Expression of VLA-4 and VLA-5 by CD38bright cells varied between patients, but the expression of VLA-4 was always equal to or greater than that of VLA-5. The ratio of VLA-4 to VLA-5 expression (VLA-4:VLA-5 ratio) was calculated and compared with the clinical features of the myeloma patients. A high VLA-4:VLA-5 ratio (> 2.0) was associated with the presence of plasmacytomas and urinary Bence-Jones protein was more common in this group. No other correlations between the clinical features of the disease and the expression of beta 1 integrins were found.
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PMID:Expression of beta 1 integrins (very late antigens-4 and -5) on myeloma cells and clinical correlates in patients with multiple myeloma. 951 75

The very late antigen (VLA)-4 and VLA-5 integrins mediate hematopoietic progenitor cell attachment to bone marrow (BM) stroma. Transforming growth factor-beta1 (TGF-beta1) is a cytokine present in the BM microenvironment that has been shown to regulate the synthesis of adhesion elements in several cell types. We have investigated whether TGF-beta1 action on human BM stromal cells affected the adhesion of progenitor cells involving integrins VLA-4 and VLA-5. Two precursor cell lines, pre-B Nalm-6 and the multipotential UT-7, attached to untreated primary stroma and to the human BM stromal cell line Str-5 preferentially using VLA-4. However, treatment of the stroma with TGF-beta1 resulted in a significant reduction in the participation of VLA-4 in mediating precursor cell adhesion to stroma and a concomitant increase in the utilization of VLA-5. This effect was not exclusive of normal BM stroma. Treatment with TGF-beta1 of stroma from multiple myeloma BM samples produced a substantial increase in VLA-5 use by the myeloma cell line NCI-H929 to adhere to this stroma. The differential use of VLA-4 and VLA-5 correlated with an increase in fibronectin surface expression by stromal cells in response to TGF-beta1. Adhesion assays to purified fibronectin using Nalm-6 cells showed a predominant utilization of VLA-4 at low concentrations of this ligand, whereas higher concentrations resulted in a preferential use of VLA-5. These results indicate that regulation of fibronectin expression on BM stromal cells by TGF-beta1 results in a modulation of the pattern of integrins used by the precursor and myeloma cells to adhere to BM stroma, which could have important consequences on the proliferation and differentiation of hematopoietic precursor cells as well as on the localization and growth of myeloma cells.
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PMID:Differential use of very late antigen-4 and -5 integrins by hematopoietic precursors and myeloma cells to adhere to transforming growth factor-beta1-treated bone marrow stroma. 957 47

B cells differentiate into plasma cells which produce antibodies in the bone marrow (BM). Multiple myeloma (MM) is a hematologic malignancy in human plasma cells, and myeloma cells grow mainly in BM. According to phenotypic differences, such as expression of adhesion molecules, human myeloma cells as well as normal plasma cells can be classified into several differentiation stages. We have found that cells strongly expressing CD38 antigens (CD38++(+)) in BM are all plasma cells, and that there also are no plasma cells in either CD38- cell fraction or fraction of cells weakly expressing CD38 antigens (CD38+). Myeloma cells in BM consist of CD38++(+)MPC-1-CD49e (VLA-5)-immature and CD38++(+)MPC-1+CD49e+ mature myeloma cells. Immature myeloma cells proliferate markedly in vitro and respond to interleukin-6 (IL-6), a growth factor for myeloma cells, whereas mature myeloma cells show very low proliferative activities and show no response to IL-6. Immature myeloma cells expressing CD21 molecules on their surface seem to attach to stromal cells in BM through binding to CD23 molecules. Thus, there is a heterogeneity in human myeloma cells, and immature myeloma cells appear to proliferate in response to IL-6.
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PMID:Biological significance of heterogeneity in human myeloma cells. 988 36

Integrin-mediated adhesion influences cell survival and may prevent programmed cell death. Little is known about how drug-sensitive tumor cell lines survive initial exposures to cytotoxic drugs and eventually select for drug-resistant populations. Factors that allow for cell survival following acute cytotoxic drug exposure may differ from drug resistance mechanisms selected for by chronic drug exposure. We show here that drug-sensitive 8226 human myeloma cells, demonstrated to express both VLA-4 (alpha4beta1) and VLA-5 (alpha5beta1) integrin fibronectin (FN) receptors, are relatively resistant to the apoptotic effects of doxorubicin and melphalan when pre-adhered to FN and compared with cells grown in suspension. This cell adhesion mediated drug resistance, or CAM-DR, was not due to reduced drug accumulation or upregulation of anti-apoptotic Bcl-2 family members. As determined by flow cytometry, myeloma cell lines selected for drug resistance, with either doxorubicin or melphalan, overexpress VLA-4. Functional assays revealed a significant increase in alpha4-mediated cell adhesion in both drug-resistant variants compared with the drug-sensitive parent line. When removed from selection pressure, drug-resistant cell lines reverted to a drug sensitive and alpha4-low phenotype. Whether VLA-4-mediated FN adhesion offers a survival advantage over VLA-5-mediated adhesion remains to be determined. In conclusion, we have demonstrated that FN-mediated adhesion confers a survival advantage for myeloma cells acutely exposed to cytotoxic drugs by inhibiting drug-induced apoptosis. This finding may explain how some cells survive initial drug exposure and eventually express classical mechanisms of drug resistance such as MDR1 overexpression.
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PMID:Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. 1002 95


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