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

The chromosomal proteins of rat liver were studied by SDS-gel electrophoresis during the process of nitrosomorpholine-induced hepatocarcinogenesis, in the primary hepatomas thus obtained, and in their metastases. It was found that an increased proteolytic activity was present in liver homogenates from carcinogen-fed animals which caused differences between the nonhistone chromosomal proteins of control and carcinogen-treated livers. These differences disappeared in the presence of the protease inhibitor PMSF. In the primary hepatomas slight quantative changes were observed: an increased amount of two proteins of 43000 and 63000 daltons molecular weight, respectively, and a decrease in the histone subfraction H 1 degrees. In the metastases both quantative and qualitative differences were detected: a strong decrease in the protein bands corresponding to the contractile proteins alpha-tubulin, beta-tubulin, and actin; an increased content of the 63000 dalton protein; the appearance of new proteins of approximately 60000, 90000, and 120000 daltons molecular weight, and the complete disappearance of histone H 1 degrees.
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PMID:Chromosomal proteins in hepatocarcinogenesis. 15 91

The influence of two proteinase inhibitors -- Trasylol (Trascolan "Polfa") and PAMBA ("Germed") -- on experimental metastases of melanotic melanoma has been studied in golden hamsters. Animals were injected intravenously with tumour cells (5x10(5) or 10(6) in 0.2 ml of saline). They obtained protease inhibitor intraperitoneally one hour prior, or one hour after melanoma cells injection. One group of hamsters were also inoculated with tumour cells preincubated 10 min. in saline containing Trasylol or PAMBA. A diminished number of experimental metastases to the lungs in each group has been observed.
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PMID:The effect of trasylol (Trascolan "Polfa") and p-aminomethylbenzoic acid (Pamba "Germed") on the experimental metastases of transplantable melanotic melanoma in golden hamster (Mesocricetus auratus, Waterhouse) 30 92

The production of protease by malignant cells has been held responsible for invasion. The effect of aprotinin, a broad-spectrum protease inhibitor, on malignant invasion was examined histologically in organotypical cocultures of precultured embryonic chick heart fragments with two human melanoma cell lines and one virus-transformed fetal mouse carcass cell line. In the presence of 400 KIU/ml aprotinin, invasion was still permissive, while in the comparison with 0.1 microgram/ml vincristine, a microtubule and directional motility inhibitor and a well-documented anti-invasive agent, invasion was completely stopped. Aprotinin remained stable in the culture medium so that the presence of invasion cannot be explained by low drug concentration. It is concluded that aprotinin-sensitive proteases are not implicated in invasion in vitro in the cell types investigated, and that this in vitro technique deserves further interest for the study of protease inhibitors in the mechanism of invasion.
Clin Exp Metastasis
PMID:The influence of the protease inhibitor aprotinin on tumor invasion of three cell lines in vitro. 244 88

Using unselected and selected B16 melanoma cell lines, we examined the relationship between homotypic aggregation properties and the potential to form experimental metastatic lung colonies. The B16 sublines were selected in vitro from a line with relatively low homotypic aggregation kinetics and experimental metastatic potential (B16-F1) by successive steps of cell aggregation, followed by separation of cell aggregates from single cells. The selected sublines possessed significantly higher rates of aggregation than did the parental cell line and, when injected intravenously as single cells, formed greater numbers of lung tumor colonies. The aggregation kinetics of the parental and selected cell lines were dependent on divalent cations, with the following order of selectivity: Ca2+ greater than Mn2+ much greater than Mg2+. Syngeneic and xenogeneic serum components and the protease inhibitor leupeptin enhanced the aggregation kinetics of various B16 cell lines. The results support the proposal that a positive correlation exists between increased homotypic adhesion and experimental metastatic potential.
Clin Exp Metastasis
PMID:Malignant melanoma cell lines selected in vitro for increased homotypic adhesion properties have increased experimental metastatic potential. 379 26

Metastasis is a characteristic and fatal feature of human malignancies. Its regulation is therefore of the utmost significance to clinicians. The present study was undertaken to determine whether a legume-derived protease inhibitor (PI) of trypsin/chymotrypsin, the field bean PI (FBPI), also has plasmin inhibitory activity and can inhibit pulmonary metastasis of B16F10 melanoma cells systemically injected into BDF1 mice. Two approaches to the problem were made. In the first, the melanoma cells were exposed to two different concentrations of the FBPI prior to their inoculation into animals. In the second, the mice were treated intraperitoneally with FBPI at a dose of 100 mg/kg body weight once daily for 10 days, the treatment being started soon after the systemic injection of the tumour cells. The study revealed that both modes of FBPI treatment could effectively block lung cell metastasis by the melanoma cells and that FBPI has plasmin blocking activity. Since urokinase type plasminogen activator and plasmin are known to play significant roles in tumour cell metastasis, the dose-dependent inhibitory effect of FBPI with antiplasmin activity on tumour cell metastasis suggests that its antimetastatogenic action is probably mediated through its plasmin inhibitory action.
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PMID:The field bean protease inhibitor has the potential to suppress B16F10 melanoma cell lung metastasis in mice. 971 30

We assessed the clinical impact of MMP-9 expression on long-term survival in patients with operable non-small cell lung cancer (NSCLC). Primary tumors of 143 consecutive patients with NSCLC resected completely and without overt distant metastases (pT1-4, pN0-2, M0, R0) were examined for MMP-9 expression using immunohistochemistry with a polyclonal, affinity-purified rabbit antibody that recognizes both latent and active MMP-9. Immunohistochemical staining of tumor cells was evaluated in comparison to normal bronchiolar epithelium that served as an internal positive control. MMP-9 expression was categorized into negative, <or=5% tumor cells stained; heterogeneous, >5% and <95% tumor cells stained; and homogeneous, >or=95% tumor cells stained at least as intensively as bronchiolar epithelium. The median follow-up period was 72 months (range = 12-144 months). Homogeneous expression of MMP-9 was observed in 26 of 143 patients (18.2%) and did not correlate with clinicopathological parameters. Relapse defined as diagnosis of distant metastasis or local recurrence was observed in 78 of the 130 (60%) patients eligible for clinical follow up analysis. Relapse led to cancer-related death in all of the 78 patients within the observation period. Kaplan-Meier analysis showed a significant association between homogeneous MMP-9 expression and shortened cancer-related survival (log-rank p = 0.016). Multivariate regression analysis including pT-status, pN-status, tumor histology and tumor grading showed an independence of this prognostic impact of homogeneous MMP-9 expression (p = 0.045). Thus, immunohistochemical evaluation of MMP-9 expression may provide a basis for the preselection of patients to be included in trials investigating specific protease inhibitor therapy after surgical resection of NSCLC.
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PMID:Prognostic impact of matrix metalloproteinase-9 in operable non-small cell lung cancer. 1249 73

RECK was first isolated as a transformation suppressor gene by cDNA expression cloning in a mouse fibroblast cell line transformed by an activated RAS oncogene. Subsequently, reduced expression of RECK in transformed cells and cancer cells were demonstrated. Moreover, in several types of tumors, positive correlation between RECK expression and survival of patients have been noted. RECK encodes a GPI-anchored glycoprotein harboring three protease inhibitor-like domains. The RECK protein regulates at least three members of the matrix metalloproteinase (MMP) family, MMP-2, MMP-9, and MT1-MMP, in vitro or in cultured cells. Restored expression of RECK in cancer cell lines results in strong suppression of invasion, metastasis, and tumor angiogenesis. Mice lacking RECK die in utero with reduced integrity of blood vessels, the neural tube, and mesenchymal tissues. In these mice, MMP activity is elevated, and the amount of collagen type I greatly reduced. The RECK null phenotype is partially rescued (half day delay of death and marked recovery of tissue integrity) by MMP-2 null mutation, demonstrating functional interaction between RECK and MMP-2 in vivo and involvement of other target(s) for RECK in the lethal phenotype. These findings indicate that (i) RECK is an important regulator of extracellular matrix remodeling and that (ii) down-regulation of RECK by oncogenic signaling leads to the excessive activation of MMPs thereby promoting malignant behavior of cancer cells such as invasion, metastasis, and angiogenesis.
Cancer Metastasis Rev
PMID:RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling. 1278 95

Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in vivo, and thus it is one of the main regulators of the fibrinolytic system. In this regard, individuals with elevated PAI-1 seem to have an increased risk for thrombotic disease, whereas those lacking the inhibitor develop a lifelong bleeding diathesis. Unexpectedly, recent observations demonstrate that cancer patients with high PAI-1 levels have a poor prognosis for survival. This correlation with metastatic disease may be related to the observation that high PAI-1 levels decrease the adhesive strength of cells for their substratum, and that this de-adhesive activity of PAI-1 is not related to its role as a protease inhibitor. Initial insights into potential mechanisms by which PAI-1 regulates the attachment, detachment, and migration of cells are addressed in this review.
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PMID:Unexpected role of plasminogen activator inhibitor 1 in cell adhesion and detachment. 1556 34

Metastasis is the primary cause of death from breast cancer. A xenograft model was used to identify genes potentially involved with metastasis, comparing expression in the poorly metastatic GI101A human breast cancer cell line and a highly metastatic variant, GILM2. cDNA microarray analyses of these isogenic variants were done using 16K Operon 70-mer oligonucleotide microarray slides. Differentially expressed genes were identified by ANOVA, and differences of > or =2.5-fold were found for 106 genes. Changes in protein or RNA expression were confirmed for 10 of 12 genes. Three markers, heat shock protein 70 (HSP-70), chemokine (C-X-C motif) ligand 1 (CXCL-1), and secreted leukocyte protease inhibitor (SLPI), were studied further with breast cancer tissue microarrays using a novel method of automated quantitative analysis. This uses cytokeratin to define pixels as breast cancer (tumor mask) within the tissue array spot and then measures intensity of marker expression using a cyanine 5-conjugated antibody within the mask. Scores were correlated with clinicopathologic variables. High HSP-70 expression and high nuclear CXCL-1 expression in primary tumors were both associated with decreased survival (P = 0.05 and 0.027, respectively). Expression of each marker was strongly associated with lymph node involvement (P = 0.0002, 0.008, 0.0012, and 0.012 for HSP-70, nuclear CXCL-1, cytoplasmic CXCL-1, and SLPI, respectively). Identification of genes associated with metastasis in experimental models may have clinical implications for the management of breast cancer, because some of these are associated with lymph node metastasis and survival and might be useful as prognostic markers or molecular targets for novel therapies.
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PMID:Using a xenograft model of human breast cancer metastasis to find genes associated with clinically aggressive disease. 1599 30

The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.
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PMID:Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. 1672 81


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