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)

Myeloma is a deadly B-cell neoplasm, characterized by the monoclonal proliferation of plasma cells, the development of osteolytic lesions, and the induction of angiogenesis. Myeloma cells are predominantly localized in the marrow where they receive the appropriate survival and proliferation signals. To reach or spread over the marrow, the myeloma cells need to migrate from the vascular to the extravascular compartment of the marrow. A process called "homing". In this review, the steps of the homing scheme, analyzed in the 5TMM model, will be described. These murine models originated from spontaneously developed myeloma in elderly mice and have since been propagated by intravenous injection of myeloma cells into young syngeneic mice. These models resemble the human condition closely. The different studies reported here demonstrate that adhesion of 5TMM cells to marrow endothelial cells is partially mediated by CD44v10 and to stromal cells by CD44v6. The 5TMM cells migrate to the marrow through the effects of MCP-1, laminin-1, and IGF-1. Once past the marrow endothelium, they invade the extravascular compartment of the marrow by secreting MMP-9 and uPA. When they have settled in the marrow, they become susceptible to the effects of IGF-1, which stimulates the cells to proliferate and produce VEGF. Furthermore, studies targeting the marrow with inhibitors will be highlighted. These studies show that the 5TMM models are useful for unraveling basic biological processes and for identifying new therapeutic targets.
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PMID:Myeloma cells (5TMM) and their interactions with the marrow microenvironment. 1531 88

Matrix metalloproteinases (MMPs) are known to play a role in cell growth, invasion, angiogenesis, metastasis, and bone degradation, all important events in the pathogenesis of cancer. Multiple myeloma is a B-cell cancer characterized by the proliferation of malignant plasma cells in the bone marrow, increased angiogenesis, and the development of osteolytic bone disease. The role of MMPs in the development of multiple myeloma is poorly understood. Using SC-964, a potent inhibitor of several MMPs (MMP-2, -3, -8, -9, and -13), we investigated the role of MMPs in the 5T2MM murine model. Reverse transcriptase-polymerase chain reaction demonstrated the presence of mRNA for MMP-2, -8, -9, and -13 in 5T2MM-diseased bone marrow. Mice bearing 5T2MM cells were given access to food containing SC-964. The concentration of SC-964 measured in the plasma of mice after 11 days of treatment was able to inhibit MMP-9 activity in gelatin zymography. Treatment of 5T2MM-bearing mice resulted in a significant reduction in tumor burden, a significant decrease in angiogenesis, and partially protective effect against the development of osteolytic bone disease. The direct role of MMPs in these different processes was confirmed by in vitro experiments. All these results support the multifunctional role of MMPs in the development of multiple myeloma.
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PMID:Multifunctional role of matrix metalloproteinases in multiple myeloma: a study in the 5T2MM mouse model. 1533 11

Multiple myeloma (MM) is an incurable plasma cell (PC) malignancy able to mediate massive destruction of the axial and craniofacial skeleton. The aim of this study was to investigate the role of the potent chemokine, stromal-derived factor-1alpha (SDF-1alpha) in the recruitment of osteoclast precursors to the bone marrow. Our studies show that MM PC produce significant levels of SDF-1alpha protein and exhibit elevated plasma levels of SDF-1alpha when compared with normal, age-matched subjects. The level of SDF-1alpha positively correlated with the presence of multiple radiological bone lesions in individuals with MM, suggesting a potential role for SDF-1alpha in osteoclast precursor recruitment and activation. To examine this further, peripheral blood-derived CD14+ osteoclast precursors were cultured in an in vitro osteoclast-potentiating culture system in the presence of recombinant human SDF-1alpha. Although failing to stimulate an increase in TRAP+, multinucleated osteoclast formation, our studies show that SDF-1alpha mediated a dramatic increase in both the number and the size of the resorption lacunae formed. The increased osteoclast motility and activation in response to SDF-1alpha was associated with an increase in the expression of a number of osteoclast activation-related genes, including RANKL, RANK, TRAP, MMP-9, CA-II, and Cathepsin K. Importantly, the small-molecule CXCR4-specific inhibitor, 4F-Benzoyl-TE14011 (T140), effectively blocked osteoclast formation stimulated by the myeloma cell line, RPMI-8226. Based on these findings, we believe that the synthesis of high levels of SDF-1alpha by MM PC may serve to recruit osteoclast precursors to local sites within the bone marrow and enhance their motility and bone-resorbing activity. Therefore, we propose that inhibition of the CXCR4-SDF-1alpha axis may provide an effective means of treatment for MM-induced osteolysis.
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PMID:Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. 1575 65

Multiple myeloma (MM) is an incurable B-cell cancer characterised by the monoclonal proliferation of tumour cells in the bone marrow (BM). It has been described that matrix metalloproteinases (MMPs) and especially MMP-9 is secreted by MM cells. In this study, we investigated the possibility to exploit MMP-9 activity to activate prodrugs and to target MM cells as a new tumour-specific therapy. Cleavage of the prodrug EV1-FITC by MMP-9 resulted in release of fluorescence which can be used as a measure of prodrug activation. The 5T33MM mouse model was used in this proof-of-principle study. The prodrug was activated in a higher amount by addition to MMP-9-producing 5T33MMvv cells, homogenates from tumour-bearing organs (BM, spleen) and isolated 5T33MM-diseased BM and spleen cells compared to non-MMP-9-producing 5T33MMvt cells and homogenates/cells from non-tumour-bearing organs/mice, as measured by fluorescence release. This fluorescence release could be inhibited by the MMP-2/MMP-9-specific inhibitor, CTT. Activation of the prodrug in the 5T33MM spleen and BM homogenates was confirmed by chromatography. EV1-fluorescein isothiocyanate injection into 5T33MM-diseased animals resulted in a higher fluorescence release by the isolated BM and spleen cells compared to injection into healthy animals. In conclusion, MMP-9 activity can be used to activate prodrugs that target MM.
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PMID:Targeting an MMP-9-activated prodrug to multiple myeloma-diseased bone marrow: a proof of principle in the 5T33MM mouse model. 1601 89

Multiple myeloma is characterized by accelerated production of the proteolytic enzyme matrix metalloproteinase (MMP)-9. We hypothesized that myeloma-produced MMP-9 may influence the rate of bone turnover in a paracrine manner. Thus, we examined the correlations of MMP-9 levels, disease severity, and bone turnover rate as evaluated by markers of bone formation and resorption. Thirty-seven newly diagnosed multiple myeloma patients (nine of Durie-Salmon stage I, 12 of stage II and 16 of stage III) and 12 age-matched controls were studied. Serum MMP-9 levels were significantly higher at stage II compared to stage I (188.78+/-91.27 vs. 59.25+/-33.09 ng/mL, p<0.004). Additionally, free urine pyridinolines (F-Pyd), free urine deoxy-pyridinolines (F-Dpd) and urine N-telopeptide fragment (NTx) were elevated, their level correlating with disease stage (p<0.001, p<0.03, p<0.001, respectively), as were bone marrow infiltration and serum interleukin-6 (IL-6) levels (p<0.0001, p<0.01, respectively). MMP-9 levels were lower in patients compared with controls (p<0.001), whereas IL-6 and bone resorption marker levels were higher in patients than in controls (p<0.001 in all cases). Significant correlation was found between infiltration, MMP-9, free urine pyd, free urine dpd and NTx for each stage of the disease (p<0.03, p<0.003, p<0.002, p<0.003 and p<0.001, respectively). Levels of MMP-9 and of IL-6 in multiple myeloma correlate well with bone turnover rate and may be useful in disease evaluation.
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PMID:Systemic levels of interleukin-6 and matrix metalloproteinase-9 in patients with multiple myeloma may be useful as prognostic indexes of bone disease. 1659 48

Malignant plasma cells in multiple myeloma home to the bone marrow (BM), accumulate in different niches and, in late disease, migrate from the BM into blood. These migratory events involve cell trafficking across extracellular matrix (ECM)-rich basement membranes and interstitial tissues. Metalloproteinases (MMP) degrade ECM and facilitate tumour cell invasion. The chemokine CXCL12 is expressed in the BM, and it was previously shown that it triggers myeloma cell migration and activation. In the present work we show that CXCL12 promotes myeloma cell invasion across Matrigel-reconstituted basement membranes and type I collagen gels. MMP-9 activity was required for invasion through Matrigel towards CXCL12, whereas TIMP-1, a MMP-9 inhibitor that we found to be expressed by myeloma and BM stromal cells, impaired the invasion. In addition, we show that the membrane-bound MT1-MMP metalloproteinase is expressed by myeloma cells and contributes to CXCL12-promoted myeloma cell invasion across Matrigel. Increase in MT1-MMP expression, as well as induction of its membrane polarization by CXCL12 in myeloma cells, might represent potential mechanisms contributing to this invasion. CXCL12-promoted invasion across type I collagen involved metalloproteinases different from MT1-MMP. These data indicate that CXCL12 could contribute to myeloma cell trafficking in the BM involving MMP-9 and MT1-MMP activities.
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PMID:Role of metalloproteinases MMP-9 and MT1-MMP in CXCL12-promoted myeloma cell invasion across basement membranes. 1627 22

Cellular interactions with microenvironmental components are critical in multiple myeloma (MM) and impede effective disease treatment. Membranal-embedded tetraspanins, associated with metastasis suppression, are underexpressed in MM. We aimed to investigate the consequences of CD81/CD82 tetraspanins over-expression in MM cell lines. CAG and RPMI 8226 were transfected with pEGFP-N1/C1 fusion vectors of CD81/CD82. Employing flow cytometry, immunocytochemistry, and activity assays we assessed transfected cells for: morphology, survival, death, caspases, cell cycle, proliferation, oxidative stress, adhesion, motility and invasion. Overexpressed CD81/CD82 pEGFP-N1 vectors reduced survival without elevation of pre-G1 or AnnexinV+/7AAD- and independently of caspases. Decreased Ki67 and elevated intracellular glutathione were detected. No perturbations in cell cycle distribution were observed. The pEGFP-C1 vectors of CD81/CD82 caused reduction of MM cell adherence with/without fibronectin, insulin-like growth factor (IGF)-I, and matrigel. They also reduced cell motility and attenuated invasion potential, expressed by reduced secreted MMP-9 activity. These novel findings delineate the significance of CD81/CD82 expression to MM cell survival and their negative effects on cell adhesion, motility, and invasion thus, supporting their role as tumor metastasis suppressors.
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PMID:Overexpression of tetraspanins affects multiple myeloma cell survival and invasive potential. 1721 Jul 82

Bone disease (BD) in multiple myeloma (MM) is because of the activation of osteoclasts and impairment of osteoblast differentiation. Connective tissue growth factor (CTGF) is known to participate in the differentiation of mesenchymal stem cells to committed osteoprogenitor cells. We analysed the concentration of circulating CTGF in 35 MM patients and 22 malignant lymphoma (ML) patients and 14 normal individuals. CTGF is protease-sensitive and thus is found as both an N-terminal half fragment (N-half CTGF) and whole (W-CTGF). Serum levels of W-CTGF and N-half CTGF + W-CTGF were determined by separate sandwich enzyme-linked immunosorbent assays. The level of W-CTGF was significantly lower (P < 0.005) in MM patients compared with ML patients and normal individuals, while N-half + W-CTGF was similar in all groups. Furthermore, W-CTGF was significantly lower in MM patients with BD compared with those without BD (P < 0.005) and this was independent of previous treatment. Matrix metalloproteinase (MMP)-9 is produced by myeloma cells and is thought to be related to BD in MM. However, MMP-9 does not cleave CTGF and serum MMP-9 level was not related to BD in MM. Thus, CTGF is an indicator of BD in MM; its metabolism and function in MM should be clarified.
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PMID:Connective tissue growth factor is an indicator of bone involvement in multiple myeloma, but matrix metalloproteinase-9 is not. 1785 5

We have investigated the production of metalloproteinases (MMP-1, MMP-2, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in bone marrow stromal cells (BMSCs) of patients with multiple myeloma (MM) and a healthy control. The new findings of this paper is that BMSCs of the MM patients exhibited intrinsic MMP-1, MMP-2 and TIMP-2 overproduction. Production of MMP-1, TIMP-2 and activation of MMP-2 was additionally enhanced in co-cultures of BMSCs with RPMI8226 cells. The ratio between MMP-2 and TIMP-2 was significantly higher in BMSCs of the MM patients than in control. BMSCs of both the control and the MM patients exhibited the presence of MMP-9 latent form, but in co-cultures RPMI8226 cells were the main producers of this metalloproteinase.
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PMID:Matrix metalloproteinases-1 and -2, and tissue inhibitor of metalloproteinase-2 production is abnormal in bone marrow stromal cells of multiple myeloma patients. 1847 60

High levels of heparanase are an indicator of poor prognosis in myeloma patients, and up-regulation of the enzyme enhances tumor growth, angiogenesis, and metastasis in animal models. At least part of the impact of heparanase in driving the aggressive tumor phenotype is due to its effect on increasing the expression and shedding of the heparan sulfate proteoglycan syndecan-1, a molecule known to promote myeloma progression. The present work demonstrated that elevation in heparanase expression in myeloma cells stimulates sustained ERK phosphorylation that in turn drives MMP-9 expression. In addition, urokinase-type plasminogen activator (uPA) and uPA receptor expression levels increased, and blocking the proteolytic activation of either MMP-9 or uPA inhibited the heparanase-induced increase in syndecan-1 shedding. Together these data provide a mechanism for heparanase-induced syndecan-1 shedding and, more importantly, demonstrate that heparanase activity in myeloma cells can lead to increased levels of proteases that are known to play important roles in the aggressive behavior of myeloma tumors. This in addition to its other known biological roles, indicates that heparanase acts as a master regulator of the aggressive tumor phenotype by up-regulating protease expression and activity within the tumor microenvironment.
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PMID:Heparanase stimulation of protease expression implicates it as a master regulator of the aggressive tumor phenotype in myeloma. 1881 15


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