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)

Recent advances in the biology of multiple myeloma cell growth and survival have suggested new avenues for treatment and potential cure of this disease. Adhesion molecules on the myeloma cell surface mediate their localization in the bone marrow via binding to extracellular matrix proteins and stromal cells. Stromal cell to tumor cell contact and the secretion of transforming growth factor by tumor cells triggers interleukin-6 secretion from stromal cells and paracrine tumor cell growth. CD40 activation of myeloma cells changes their cell surface phenotype, triggers autocrine interleukin-6 secretion, and can regulate myeloma cell cycle in a p53-dependent fashion. Interleukin-6 is both a growth and survival factor for myeloma cells, and delineation of the signaling cascades mediating its effects permits the development of novel therapies either to interrupt growth or trigger apoptosis. New immune therapies offer the opportunity to treat minimal residual disease after stem cell transplantation, thereby improving outcome. Selected donor lymphocyte infusions after allografting and infusion of activated autologous T cells following autografting are examples of adoptive immunotherapy. Myeloma cell to dendritic cell fusions have been used in a vaccination strategy both to prevent and treat myeloma in an animal model, providing the rationale for similar clinical trials in humans. For the first time, a variety of novel treatment strategies derived from advances in understanding the disease pathogenesis offer the potential to achieve long-term disease-free survival in patients with multiple myeloma.
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PMID:Advances in the biology of multiple myeloma: therapeutic applications. 1052 90

Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a member of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNF alpha, UV light and increases in intracellular calcium levels. However, the function of RAFTK remains largely unknown. Our previous studies demonstrated that treatment with dexamethasone (Dex), ionizing radiation (IR), and anti-Fas mAb induces apoptosis in multiple myeloma (MM) cells. In the present study, we examined the potential role of RAFTK during induction of apoptosis in human MM cells triggered by these three stimuli. Dex-induced apoptosis, in contrast to apoptosis triggered by anti-Fas mAb or IR, is associated with activation of RAFTK. Transient overexpression of RAFTK wild type (RAFTK WT) induces apoptosis, whereas transient overexpression of Kinase inactive RAFTK (RAFTK K-M) blocks Dex-induced apoptosis. In contrast, transient overexpression of RAFTK K-M has no effect on apoptosis triggered by IR or Fas. In Dex-resistant cells, Dex does not trigger either RAFTK activation or apoptosis. Finally, interleukin-6 (IL-6), a known survival factor for MM cells, inhibits both activation of RAFTK and apoptosis of MM.1S cells triggered by Dex. Our studies therefore demonstrate Dex-induced RAFTK-dependent, and IR or Fas induced RAFTK-independent apoptotic signaling cascades in MM cells.
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PMID:RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. 1059 81

One of the main characteristics of multiple myeloma cells is their predominant localization in the bone marrow. It is, however, unclear whether this is due to a selective initial entry, or whether this entry is more random and other processes like survival and/or growth stimulation, only present in the medullar microenvironment, are unique. To investigate this, in vivo homing kinetics of murine 5T2MM cells shortly after injection were assessed in bone marrow, liver, spleen, lungs, heart, intestines, kidney and testis by tracing of radiolabelled cells, by immunostaining of isolated cells and by polymerase chain reaction analysis. We demonstrated the presence of 5T2MM cells in bone marrow, spleen and liver with all other organs being negative. Adhesion assays of 5T2MM cells to different types of endothelial cells demonstrated a selective adhesion of 5T2MM cells to bone marrow and liver and not to lung endothelial cells. We here demonstrate that the specific in vivo localization of the 5T2MM cells is a result of the combination of a selective entry/adhesion of the 5T2MM cells in the bone marrow, spleen and liver, and a selective survival and growth of these tumour cells in the bone marrow and spleen but not in the liver.
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PMID:Selective initial in vivo homing pattern of 5T2 multiple myeloma cells in the C57BL/KalwRij mouse. 1073 71

MDC-9 is a widely expressed member of the metalloproteinase/disintegrin/cysteine-rich protein family. The disintegrin domain of MDC-9 lacks an RGD motif but has recently been reported to bind the alpha(6)beta(1) integrin; however, it is unclear whether MDC-9 can bind other integrins. In the present study myeloma cells, but not lymphoblastoid cells, were shown to bind to immobilised, recombinantly expressed MDC-9 disintegrin domain (A9dis). Binding was divalent cation-dependent, being supported by Mn(2+) and Ca(2+). Adhesion of myeloma cells to A9dis was completely inhibited by an antibody to the alpha(v)beta(5) integrin but not by antibodies to other subunits. RGD-containing peptides had no effect on binding, suggesting that MDC-9 interacts with alpha(v)beta(5) in an RGD-independent manner. Flow cytometric analyses demonstrated that myeloma cells, but not lymphoblastoid cells, expressed alpha(v)beta(5) on the cell membrane. These data indicated that the disintegrin domain of MDC-9 can function as an adhesion molecule by interacting with an alpha(v)beta(5) integrin.
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PMID:MDC-9 (ADAM-9/Meltrin gamma) functions as an adhesion molecule by binding the alpha(v)beta(5) integrin. 1116 58

The tumor microenvironment is often overlooked when considering tumor response to chemotherapeutic agents. This environment consists of soluble factors, components of the extracellular matrix as well as cell-cell interactions. Recently, it has become clear that cell-cell and cell-matrix interactions result in cytoskeletal reorganization and the activation of multiple signal transduction pathways that directly influence cell survival, growth and differentiation. Experimental evidence shows that anti-apoptotic pathways initiated by cell adhesion are operative in tumor cells and, furthermore, cause resistance to mechanistically distinct cytotoxics. For hematopoietic tumors, cell adhesion to a single matrix, fibronectin is sufficient to inhibit apoptosis induced by mechanistically distinct cyctotoxics. Adhesion of hematopoietic tumors to this matrix blocks cell cycle progression, and for the human multiple myeloma 8226 cell line adhesion to fibronectin resulted in increased p27kip1 levels, which correlated with cell cycle arrest and drug resistance. A decrease in initial DNA damage induced by topoisomerase II inhibitors has also been observed in adherent hematopoietic tumor cell lines. Further studies investigating the mechanisms of cell adhesion mediated drug resistance may reveal novel targets directed at the reversal of de novo drug resistance.
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PMID:Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies. 1183 46

Apoptosis is a regulated event crucial to the development and proliferation of normal and malignant B cells. We have studied the role of signals delivered via alpha4 integrin on apoptosis triggered by three different pathways on these cells. For apoptosis induced by serum deprivation, culturing B cells on the recombinant fibronectin fragment H89, a known ligand for alpha4beta1 integrin, resulted in statistically significant (P < 0.005) higher viability values (68%, 65% and 67%) for Ramos, Nalm-6 and EHEB cells, respectively, than culturing cells on poly lysine (42%, 42% and 48%). An antialpha4 MoAb reverted the protecting effect, thus confirming that it was due specifically to alpha4 engagement. Similarly, cells cultured on FN-III4-5, a recently identified fibronectin region which binds activated alpha4 integrin, also showed statistically significant higher viability than poly lysine cultures. Alpha4 engagement however, did not prevent apoptosis induced on Ramos cells via surface IgM. Adhesion of IM-9 cells, a myeloma cell line carrying functional Fas receptors, to the H89 fragment neither increased cell viability upon triggering apoptosis via Fas when compared to poly lysine. These results indicate that alpha4 signalling may overcome B cell apoptosis induced by the lack of growth factors but does not seem to affect the IgM or Fas apoptotic pathways, thus suggesting different intracellular mechanisms for these processes.
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PMID:Adhesion to fibronectin via alpha4 integrin (CD49d) protects B cells from apoptosis induced by serum deprivation but not via IgM or Fas/Apo-1 receptors. 1196 61

Acquired drug resistance continues to be one of the major obstacles hindering the successful treatment of many forms of cancer. Compounds utilized as antagonists of these cytoprotective mechanisms have, for the most part, proven to be ineffective at overcoming clinical resistance to cytotoxic drugs. Recently, the tumor cell microenvironment has been found to have a significant bearing on the survival of tumor cells following exposure to a wide variety of anti-neoplastic agents, prior to the acquisition of known drug resistance mechanisms. Specifically, interactions between cell surface integrins and extracellular matrix components have been shown to be responsible for this phenomenon of innate drug resistance, which we have termed Cell Adhesion Mediated Drug Resistance, or CAM-DR. Following its discovery using a multiple myeloma cell line model, evidence for CAM-DR has been found in a multitude of other human tumor cell types. In contrast to many other drug resistance mechanisms, integrin-mediated cell signaling is capable of protecting against death induced by an extremely wide variety of structurally and functionally diverse agents from traditional DNA damaging agents to the promising novel kinase inhibitor STI-571. This review examines the role of integrins in regard to their ability to protect tumor cells from drug- and radiation-induced apoptosis through numerous intracellular mechanisms. Current and future antagonists of specific integrin heterodimers may have the potential to sensitize tumor cells when used in combination with standard chemotherapy regimens. Specific signal transduction pathways initiated by integrin ligation will also be discussed as potential bridge points for inhibiting cell survival during cytotoxic drug exposure.
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PMID:Integrins as novel drug targets for overcoming innate drug resistance. 1218 19

Malignant plasma cells (PC) from multiple myeloma (MM) patients characteristically home to the bone marrow (BM). High numbers of tumour cells are found in the peripheral blood (PB) only at end-stage disease (secondary plasma cell leukaemia, PCL) in a minority of patients. Using flow cytometric and fluorescence in situ hybridization (FISH) analysis, a high percentage of tumoral BM PC from untreated patients was found to express CD106. In addition, these cells also expressed an activated form of CD29, as determined using the CD29 activation reporter monoclonal antibody HUTS-21. Adhesion-binding experiments showed that CD106+-activated CD29+ BM PC from these patients adhered to fibronectin (FN) in a CD29/CD49d-dependent manner. In contrast, marrow PC from progressive patients and BM or circulating malignant cells from secondary PCL patients expressed lower levels or were negative for CD106 and activated CD29, respectively, with a decreased or zero ability to adhere to FN. The expression of constitutive CD29 and CD49d, however, was similar during disease progression. We conclude that BM myelomatous cells co-express CD106 and a functionally active form of CD29. Moreover, our results suggest that the loss of expression and/or function of these antigens are associated with the progression of MM and may explain the exit of tumoral cells from the BM.
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PMID:CD106 and activated-CD29 are expressed on myelomatous bone marrow plasma cells and their downregulation is associated with tumour progression. 1235 5

To address the urgent need for novel therapies for multiple myeloma (MM), long-term research efforts have characterized the mechanisms whereby MM cells home to the bone marrow and adhere to bone marrow stromal cells and extracellular matrix proteins. Research also characterizes the functional sequelae of this binding to identify targets for novel therapies. This article describes the mechanisms by which MM cells home to bone marrow and adhere to bone marrow stromal cells and extracellular matrix proteins, and describes the functional sequelae of this binding. Adhesion molecules that mediate MM cell binding to bone marrow stromal cells are identified, and the growth and survival advantage conferred by this binding is discussed. The biologic significance of cytokines in MM pathogenesis and the signaling cascades mediating their effects are delineated. Apoptotic and targeted therapeutic strategies to overcome drug resistance based on interrupting growth or triggering apoptotic-signaling cascades also are identified, providing the basis for novel biologically based therapies, such as thalidomide/immunomodulatory drugs and proteasome inhibitor PS-341.
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PMID:Moving disease biology from the laboratory to the clinic. 1252 Apr 80

Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key roles in homing and mobilization of hematopoietic stem cells (HSC). Active signaling through SDF-1/CXCR4 and upregulation of adhesion molecules are required for homing, whereas downregulation of adhesion molecules and disruption of SDF-1/CXCR4 signaling are required for mobilization of HSC. We studied the surface expression of CXCR4 very late activation antigen (VLA)-4 and VLA-5 on myeloma cells mobilized with cyclophosphamide and GM-CSF in 12 multiple myeloma patients undergoing HSC mobilization for autologous transplantation. We also studied the plasma levels of SDF-1 in apheresis collection of these patients. We observed a statistically significant decrease in the levels of SDF-1 and surface expression of CXCR4 on myeloma cells in four consecutive apheresis collections compared with premobilization bone marrow specimens. We also observed a statistically significant decrease in surface expression of VLA-4 in myeloma cells in the apheresis collections compared with premobilization bone marrow samples. Furthermore, myeloma cells derived from apheresis collections had decreased adhesion and trans-stromal migration in response to SDF-1, which could be reversed by short incubation with interleukin-6. Hence, mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4.
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PMID:Mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4. 1468 92


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