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

Metastatic cancer cells, like trophoblasts of the developing placenta, are invasive and must escape immune surveillance to survive. Complement has long been thought to play a significant role in the tumor surveillance mechanism. Bone sialoprotein (BSP) and osteopontin (OPN, ETA-1) are expressed by trophoblasts and are strongly up-regulated by many tumors. Indeed, BSP has been shown to be a positive indicator of the invasive potential of some tumors. In this report, we show that BSP and OPN form rapid and tight complexes with complement Factor H. Besides its key role in regulating complement-mediated cell lysis, Factor H also appears to play a role when "hijacked" by invading organisms in enabling cellular evasion of complement. We have investigated whether BSP and OPN may play a similar role in tumor cell complement evasion by testing to see whether these glycoproteins could promote tumor cell survival. Recombinant OPN and BSP can protect murine erythroleukemia cells from attack by human complement as well as human MCF-7 breast cancer cells and U-266 myeloma cells from attack by guinea pig complement. The mechanism of this gain of function by tumor cell expression of BSP or OPN has been defined using specific peptides and antibodies to block BSP and OPN protective activity. The expression of BSP and OPN in tumor cells provides a selective advantage for survival via initial binding to alpha(V)beta(3) integrin (both) or CD44 (OPN) on the cell surface, followed by sequestration of Factor H to the cell surface and inhibition of complement-mediated cell lysis.
 ...
PMID:Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. 1074 89

In this study, we examined osteopontin (OPN) production in myeloma cells and plasma OPN levels in multiple myeloma (MM) patients. We assessed OPN production in bone marrow cells (BMCs) by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA). We also assessed OPN production in various B-cell malignant cell lines, including three myeloma cell lines by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. In addition, we measured plasma OPN concentrations by ELISA in 30 MM patients, 21 monoclonal gammopathy of undetermined significance (MGUS) patients and 30 healthy volunteers. As a result, in an immunocytochemical study, abundant OPN was detected in BMCs from overt MM patients, whereas no OPN was detected in BMCs from patients with other haematological diseases, including MGUS. Cultured BMCs from overt MM patients produced more OPN than those from patients with either smouldering MM or MGUS. Myeloma cell lines spontaneously produced OPN. Plasma OPN levels of MM patients were significantly higher than those of MGUS patients and healthy volunteers (P < 0.05). Moreover, they correlated with both progression and bone destruction of the disease (P < 0.05). These suggest that myeloma cells actively produce OPN, which possibly contributes to osteoclastic bone resorption in MM. Plasma OPN levels may be a useful biomarker for assessing bone destruction in MM and distinguishing MM from MGUS or smouldering MM.
 ...
PMID:Enhanced production of osteopontin in multiple myeloma: clinical and pathogenic implications. 1453 7

Multiple myeloma (MM) expands in the bone marrow and causes devastating bone destruction by enhancing osteoclastic bone resorption in its vicinity, suggesting a close interaction between MM cells and osteoclasts (OCs). Here, we show that peripheral blood mononuclear cell-derived OCs enhanced growth and survival of primary MM cells as well as MM cell lines more potently than stromal cells, and that OCs protected MM cells from apoptosis induced by serum depletion or doxorubicin. OCs produced osteopontin (OPN) and interleukin 6 (IL-6), and adhesion of MM cells to OCs increased IL-6 production from OCs. In addition, IL-6 and OPN in combination enhanced MM cell growth and survival. However, the effects of OCs on MM cell growth and survival were only partially suppressed by a simultaneous addition of anti-IL-6 and anti-OPN antibodies and were completely abrogated by inhibition of cellular contact between MM cells and OCs. These results demonstrate that OCs enhance MM cell growth and survival through a cell-cell contact-mediated mechanism that is partially dependent on IL-6 and OPN. It is suggested that interactions of MM cells with OCs augment MM growth and survival and, thereby, form a vicious cycle, leading to extensive bone destruction and MM cell expansion.
 ...
PMID:Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. 1518 21

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
 ...
PMID:The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. 1607 95

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.
 ...
PMID:Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients. 1620 9

Multiple myeloma is characterized by the accumulation of clonal malignant plasma cells in the bone marrow, which stimulates bone destruction by osteoclasts and reduces bone formation by osteoblasts. In turn, the changed bone microenvironment sustains survival of myeloma cells. Therefore, a challenge for treating multiple myeloma is discovering drugs targeting not only myeloma cells but also osteoclasts and osteoblasts. Because resveratrol (trans-3,4',5-trihydroxystilbene) is reported to display antitumor activities on a variety of human cancer cells, we investigated the effects of this natural compound on myeloma and bone cells. We found that resveratrol reduces dose-dependently the growth of myeloma cell lines (RPMI 8226 and OPM-2) by a mechanism involving cell apoptosis. In cultures of human primary monocytes, resveratrol inhibits dose-dependently receptor activator of nuclear factor-kappaB (NF-kappaB) ligand-induced formation of tartrate-resistant acid phosphatase (TRACP)-positive multinucleated cells, TRACP activity in the medium, up-regulation of cathepsin K gene expression, and bone resorption. These inhibitions are associated with a down-regulation of RANK expression at both mRNA and cell surface protein levels and a decrease of NFATc1 stimulation and NF-kappaB nuclear translocation, whereas the gene expression of c-fms, CD14, and CD11a is up-regulated. Finally, resveratrol promotes dose-dependently the expression of osteoblast markers like osteocalcin and osteopontin in human bone marrow mesenchymal stem cells (hMSC-TERT) and stimulates their response to 1,25(OH)2 vitamin D3 [1,25(OH)2D3]. Moreover, resveratrol up-regulates dose-dependently the expression of 1,25(OH)2D3 nuclear receptor. Taken together, these results suggest that resveratrol or its derivatives deserve attention as potential drugs for treating multiple myeloma.
 ...
PMID:Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. 1626 19

Multiple myeloma (MM) is a malignancy characterised by the accumulation of monoclonal plasma cells in the bone marrow. Different reports indicate the expression of CD44 variant isoforms (CD44v) by MM cells. Osteopontin (OPN), which is expressed by MM cells, is known to be a ligand for CD44v6. In this study, we investigated the role of OPN with emphasis on a functional correlation between OPN and CD44v in the 5T33MM model. Our group reported the expression of CD44v by 5T33MM cells. Using this model, we have demonstrated the secretion of OPN by 5T33MM cells. OPN affected 5T33MM cell survival by increasing proliferation and inhibiting apoptosis. OPN also stimulated 5T33MM cell migration, transendothelial migration and matrix metalloproteinase-9 activity. We confirmed the proliferative and migratory effects of OPN on human MM cells. By applying inhibiting anti-CD44v6 antibodies, we found that OPN stimulated cell proliferation by engaging this isoform. Anti-CD44v antibodies and RGD peptides both inhibited cell migration, suggesting an involvement of both, CD44v isoforms and integrins. In conclusion, OPN may act as a mediator of MM cell survival by engaging CD44v. The protein is further involved in migration and invasion of MM cells through the activation of either alphavbeta3 integrin or CD44v isoforms.
 ...
PMID:The involvement of osteopontin and its receptors in multiple myeloma cell survival, migration and invasion in the murine 5T33MM model. 1641 19

Osteolytic bone disease is a major clinical feature of multiple myeloma (MM). Mechanisms of bone destruction are related to increased osteoclastic activity, which is not accompanied by a comparable increase in bone formation, as osteoblasts are functionally exhausted. Thus the lesions rarely heal and bone scans are often negative in myeloma patients with extensive lytic lesions, offering very little in the follow-up of bone disease. Biochemical markers of bone resorption, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), tartrate resistant acid phosphatase isoform-5b, bone formation (bone-specific alkaline phosphatase [BAP]), and osteocalcin provide useful information on bone dynamics. Several studies have shown that NTX, CTX, and ICTP are elevated in myeloma patients, reflect the extent of bone disease, and correlate with survival. Furthermore, they are useful in monitoring bone destruction during antimyeloma or bisphosphonate treatment. Markers of bone formation have produced conflicting results in trials. However, BAP correlates with bone pain, lytic lesions, and fractures in quite a few studies of MM. Novel markers, such as bone sialoprotein, receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin, osteopontin, dickkopf-1, and soluble Frizzle-related protein-2 have been found of value in assessing bone lytic disease in MM, but their promising results must be confirmed in large trials. In conclusion, although no marker provides optimal analysis of MM or of MM treatments, combinations of markers have at times helped in assessing MM stages and lytic bone disease and in monitoring specific treatment modalities. The need for further research in this field is clear.
 ...
PMID:Biochemical markers of bone metabolism in multiple myeloma. 1668 Aug 33

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. MM cells enhance bone resorption by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the bone marrow. Macrophage inflammatory protein (MIP)-1alpha and (MIP)-1beta are secreted by MM cells, and play a major role in the enhancement of bone resorption by MM cells. Furthermore, the growth and survival of MM cells are enhanced by contact with osteoclasts (OCs) suggesting the presence of a vicious cycle between OCs and MM cells. OCs also enhance angiogenesis in concert with MM cells largely through the cooperative actions of osteopontin from OCs and VEGF from MM cells. The angiogenic effect may further facilitate the vicious cycle between bone destruction and MM cell expansion. In addition, MM cells secrete soluble factor(s) to suppress bone formation. Secreted Frizzled-related protein (sFRP)-2, an inhibitor of Wingless type (Wnt) binding to Frizzled, is produced by most MM cells, and immunodepletion of sFRP-2 abrogates the inhibition of bone formation. Thus, MM cells enhance bone resorption and suppress bone formation to cause destructive bone lesions. Further elucidation of the mechanism of bone destruction by MM may lead to a novel therapeutic approach to prevent bone destruction and tumor growth.
 ...
PMID:Bone destruction in multiple myeloma. 1683 32

The production of mature blood cells within the bone marrow (BM) is attributed to a pool of haemopoietic stem cells (HSC). It is now evident that HSC reside preferentially at the endosteal region within the BM where bone-lining osteoblasts are a key cellular component of the HSC niche that directly regulates HSC fate. Osteoblasts synthesise proteins that stimulate and inhibit HSC proliferation. In addition to angiopoietin 1 (Ang-1), osteoblasts synthesise and express the highly acidic glycoprotein, osteopontin (Opn), which, like Ang-1, acts as a potent constraining factor on HSC proliferation. Overexpression of Opn is a feature of haemopoietic malignancies, such as multiple myeloma and chronic myeloid leukaemia, although its exact role in the aetiology and progression of these diseases remains unclear. Through osteoblasts and their cell surface and expressed proteins including Opn, bone is able to regulate the tissue that resides within it. In doing so, Opn can be considered a bridge between bone and blood.
 ...
PMID:Osteopontin: a bridge between bone and blood. 1684 93


1 2 3 4 Next >>