Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinase (MMP)-9 (gelatinase B) belongs to the MMP family of zinc-dependent endopeptidases that has been associated with tumor cell invasion and metastasis and tumor-induced angiogenesis. As a secreted MMP, pro-MMP-9 is released into the extracellular environment by both tumor and stroma cells, where it fulfills its proteolytic functions degrading both extracellular matrix (ECM) and non-ECM proteins. A major dilemma in our understanding of MMP-9 function is how the released protease is targeted to the right location and how its activity is controlled at the pericellular space. It has been proposed that MMP-9 interact with cell surface components and that this type of interaction positively regulates enzymatic activation and activity. However, recent evidence shows that association of MMP-9 with the cell surface is mediated by a distinct array of surface proteins that serve to regulate multiple aspects of the enzyme function including localization, inhibition and internalization. How these distinct mechanisms regulate the overall MMP-9 activity at the pericellular space remains an important goal in our understanding of MMP-9 function at the cell surface. Furthermore, the study of surface-associated MMP-9 imposes new conceptual and methodological challenges with particular consideration to the unique structural and functional characteristics of this key enzyme.
Cancer Metastasis Rev
PMID:Cell surface association of matrix metalloproteinase-9 (gelatinase B). 1278 94

The ZmpC zinc metalloproteinase of Streptococcus pneumoniae, annotated in the type 4 genome as SP0071, was found to cleave human matrix metalloproteinase 9 (MMP-9). The previously described IgA protease activity was confirmed to be specifically linked to the IgA1-protease/SP1154 zinc metalloproteinase. MMP-9 is a protease cleaving extracellular matrix gelatin and collagen and is activated by proteolytic cleavage like most proteases. MMP-9 is a human protease and is involved in a variety of physiological and pathological matrix degrading processes, including tissue invasion of metastases and opening of the blood-brain barrier. While TIGR4 (serotype 4) and G54 (serotype 19) pneumococcal genome strains have a highly conserved copy of zmpC, the genome of R6 (a derivative of serotype 2 D39 strain) lacks zmpC. Both the analysis for zmpC presence and MMP-9 cleavage activity in various pneumococcal strains showed correlation of ZmpC with MMP-9 cleavage activity. When assaying clinical isolates of S. pneumoniae, the zmpC gene was not found in any of the nasal and conjunctival swab isolates, but it was present in 1 out of 13 meningitis isolates and in 6 out of 11 pneumonia isolates. In a murine pneumonia model, infection with a zmpC-mutant reduced mortality at 3-4 days post-infection by 75%, when compared with infection with wild-type strains. These data indicate that the ZmpC pneumococcal protease may play a role in pneumococcal virulence and pathogenicity in the lung.
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PMID:Pneumococcal zinc metalloproteinase ZmpC cleaves human matrix metalloproteinase 9 and is a virulence factor in experimental pneumonia. 1286 60

We have utilized oligonucleotide microarrays to identify novel genes of potential clinical and biological importance in prostate cancer. RNA from 74 prostate cancers and 164 normal body samples representing 40 different tissues were analysed using a customized Affymetrix GeneChip oligonucleotide microarray representative of over 90% of the expressed human genome. The gene for the zinc transporter ZnT4 was one of several genes that displayed significantly higher expression in prostate cancer compared to normal tissues from other organs. A polyclonal antipeptide antibody was used to demonstrate ZnT4 expression in the epithelium of all 165 elements of benign and 326 elements of localized prostate cancers examined and in nine of 10 advanced prostate cancer specimens by immunohistochemistry. Interestingly, decreased intensity of ZnT4 immunoreactivity occurred in the progression from benign to invasive localized prostate cancer and to metastatic disease. Immunofluorescence analysis and surface biotinylation studies of cells expressing ZnT4 localised the protein to intracellular vesicles and to the plasma membrane. These findings are consistent with a role for ZnT4 in vesicular transport of zinc to the cell membrane and potentially in efflux of zinc in the prostate.
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PMID:Expression of the zinc transporter ZnT4 is decreased in the progression from early prostate disease to invasive prostate cancer. 1295 79

Endostatin, a potent endogenous inhibitor of angiogenesis, inhibits the growth of primary tumors without induction of acquired drug resistance in mice. We report that a soluble recombinant human (rh) Endostatin produced with characteristics of the native Endostatin, effectively inhibited the growth of primary tumors and pulmonary metastases in a dose-dependent manner. We also show that deletion of two of the four zinc ligands of rhEndostatin did not affect this potent tumor inhibiton. The growth of established Lewis lung primary tumors implanted into mice was inhibited (80-90%) upon systemic treatment with 50 mg/kg/12 h of rhEndostatin. Using the B16-BL6 murine experimental pulmonary metastases model, rhEndostatin administered at 1.5 mg/kg/day or 4.5 mg/kg/day beginning 3- or 11-days post tumor cell injection, respectively, resulted in an approximate 80% inhibition of tumor growth. At effective anti-tumor doses of 1.5 and 50 mg/kg, pharmacokinetic modeling in mice showed (a) the protein was 100% bioavailable, (b) the AUC ranged from 16 to 700 ng ml/h and (c) the Cmax ranged from 161 to 4582 ng/ml. At the highest dose tested (300 mg/kg), delivered as a single bolus, no drug-related toxicity was observed in a Cynomolgus monkey infused with rhEndostatin. No toxicity was observed even at AUC and Cmax values that were 1.3- to 56-fold higher than those observed in mice with tumors that were potently inhibited. Our production system yields a well characterized, soluble and potent rhEndostatin at quantities sufficient for human use. The preclinical studies described herein are an important first step toward the assessment of Endostatin in the clinic.
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PMID:Zinc ligand-disrupted recombinant human Endostatin: potent inhibition of tumor growth, safety and pharmacokinetic profile. 1451 43

It has recently been reported that not only endogenous nitric oxide (NO) but also carbon monoxide (CO) produced by heme oxygenase (HO) have many physiological functions. The objective of the present study was to determine whether endogenous NO or CO is involved in the experimental pulmonary or liver metastasis of colon cancer in mice. Intravenous or intrasplenic injection of colon 26 cells from a mouse colon adenocarcinoma cell line resulted in multiple pulmonary or liver metastases. NG-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase (NOS), or zinc deuteroporphyrin 2, 4-bis glycol (ZnDPBG), a competitive inhibitor of HO, was administered to the mice only on the day of tumor inoculation. We assessed the number of tumor cells 24 h later and the outcome of metastases of the target organ. In the pulmonary metastasis model, L-NAME increased both the number of tumor cells 24 h later and outcome of metastases 18 days later, but did not have a significant effect on liver metastasis. On the other hand, metastasis to the liver, but not that to the lung, increased following administration of ZnDPBG. These results suggest that the activities of NOS and HO could influence experimental metastasis in an organ-specific manner.
Clin Exp Metastasis 2003
PMID:Different effects of constitutive nitric oxide synthase and heme oxygenase on pulmonary or liver metastasis of colon cancer in mice. 1452 34

Aminopeptidase N (APN/CD13), a Zn2+-dependent ectopeptidase, is localized on the cell surface and functions as a transmembrane protein. Increased expression and activity of APN have been postulated to correlate with the aggressive behavior of several tumor types. In this study, the osteosarcoma cell line MNNG/HOS was stably transfected with an expression vector capable of expressing the antisense transcript of APN. Four stably transfected clones, the control clones and parental cells were characterized. Stable integration of the antisense vector was confirmed by PCR analysis of genomic DNA. Competitive RT-PCR revealed that mRNA expression of antisense-transfectants was decreased to approximately 37% of the control cell line. The activity assay showed that the enzymatic activity of APN was inhibited to approximately 51% of the control cell line. Antisense-transfection had no influence on the cellular proliferation measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, on the motility in Transwell chambers, and on the adhesive potential to collagen I. However, an in vitro invasion assay revealed a significant decrease in the number of cells that migrated through a reconstituted membrane (51% of the control cell line). The adhesive potential to Matrigel was also affected (73% of the control cell line). Furthermore, under in vivo conditions, a reduced potency to metastasize to the lung was shown in an experimental metastasis assay in nude mice. These findings demonstrate that APN plays an active role in the cellular attachment and proteolytic degradation of the extracellular matrix in the metastatic process of osteosarcomas.
Clin Exp Metastasis 2003
PMID:Inhibitory effect of antisense aminopeptidase N (APN/CD13) cDNA transfection on the invasive potential of osteosarcoma cells. 1466 89

Considerable evidence has implicated matrix metalloproteinases (MMPs), a group of zinc-dependent endopeptidases, in the degradation of extracellular matrix (ECM) during the metastatic process. Most MMPs are secreted as inactive zymogens and are activated extracellularly. Over expression of MMP-1, -2, -3. -7, -9, -13, and MT1-MMP has been demonstrated in human colorectal cancers. The degree of over expression of some MMPs has been noted to correlate with stage of disease and/or prognosis. An unresolved debate has centered on whether MMPs are produced by the stromal cells surrounding a tumor or by the colorectal cancer cells themselves. MMP-7 is produced abundantly by colorectal cancer cells. The presence of a mutation in the APC gene results in nuclear accumulation of the beta-Catenin/TCF complex, which serves as a transcriptional factor that upregulates MMP-7 expression. Increased expression of MMP-3 in colorectal cancer correlates with low levels of microsatelite instability and poor prognosis. Increased levels of MMP-9 (produced primarily by inflammatory cells) have been demonstrated early in the transition from colon adenoma to adenocarcinoma. In contrast to other MMPs, overexpression of MMP-12 is associated with increased survival in colorectal cancer, presumably as a result of an inhibitory effect on angiogenesis. Based on the assumption that MMPs were responsible for metastasis, several orally active, low molecular weight inhibitors of MMPs (MMPIs) have been developed. These MMPIs have been effective in controlling cancer progression in animals, but have failed to prolong survival in phase III clinical trials in patients with advanced cancer. MMPIs have not yet been evaluated in patients with colorectal cancer.
Cancer Metastasis Rev
PMID:Role of matrix metalloproteinases (MMPs) in colorectal cancer. 1500 Jan 52

We studied the serum levels of vitamins A, E, zinc and copper in two hundred and twenty-five subjects of both sexes. They were divided into two groups: 87 healthy subjects who served as controls and 138 patients with neoplastic disease. The patients were subdivided according to the absence (n = 79) or the presence of metastatic disease (n =59). In 59 patients with cancer, who were in therapy with scavenger drugs of free radical such as calcium antagonists and the antagonists of receptors H2, we also studied the possible effect of the same therapy on the serum levels of vitamins, on the concentrations of the microelements and on membrane lipid peroxidation. We found that membrane lipid peroxidation, evaluated from the time of in vitro formation in the blood of so-called "Heinz bodies," decreased in all patients treated with scavenger drugs. In these patients the permeability of the erythrocyte membrane was similar to the controls and the serum levels of the vitamins were equal to the levels in patients who did not receive these therapies. Zinc concentration increased while copper remained unchanged. We also studied the levels of vitamins in some organs. The results are discussed considering the role of free radicals. We underline the importance of vitamins A and E in the protection from membranous peroxidation and from free radicals and the need to consider cancer as a systemic morbid event, apart from the contingent actual location.
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PMID:Vitamins A, E, microelements and membrane lipid peroxidation in patients with neoplastic disease treated with calcium antagonists and antagonists of receptors H2. 1527 9

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.
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PMID:Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. 1536 99

The functions of the Snail family of zinc-finger transcription factors are essential during embryonic development. One of their best-known functions is to induce epithelial to mesenchymal transitions (EMTs), which convert epithelial cells into migratory mesenchymal cells. In recent years, many orthologues of the Snail family have been identified throughout the animal kingdom, and their study is providing new clues about the EMT-dependent and -independent functions of Snail proteins. Here, we discuss these functions and how they influence cell behaviour during development and during diseases such as metastatic cancer. From these findings, we propose that Snail genes act primarily as survival factors and inducers of cell movement, rather than as inducers of EMT or cell fate.
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PMID:The Snail genes as inducers of cell movement and survival: implications in development and cancer. 1598


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