Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of the synthetic matrix metalloproteinase inhibitor batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent. Administration of batimastat (6 x 30 mg/kg i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung colonies following i.v. inoculation of cells. This implies an effect both on seeding efficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgical removal) significantly inhibited lung metastasis but had little effect on lymphatic metastasis. However, when treatment was initiated 2 days prior to surgery and continued until day 70, 100% of animals survived to day 120 when there was no evidence of metastatic disease. All control animals (n = 25) in two separate experiments died before day 100 with lymphatic, lung, and extrapulmonary metastases. Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular invasion, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing sustained tumor-free survival.
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PMID:Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94). 866 19

Matrix metalloproteinases (MMPs) play an important role in cancer cell invasion by degrading extracellular matrix proteins. However, little is known about the in situ expression of MMP in human normal livers and primary liver tumors. In this study, we therefore examined the in situ expression of immunoreactive MMP and tissue inhibitors of MMP (TIMP) in 10 normal livers, 11 surgically resected intrahepatic cholangiocarcinomas (CCs), and 6 surgically resected hepatocellular carcinomas (HCCs). In normal livers, MMP and TIMP were infrequently and faintly expressed in bile ducts, but were not expressed in hepatocytes. In the 11 CCs, MMP-1, MMP-2, MMP3, MMP-9, TIMP-1, and TIMP-2 were expressed in tumor cells and/or tumor stroma in 11 (100%), 5 (45%), 8 (73%), 3 (27%), 9 (82%), and 9 (82%), respectively. The expression of MMP and TIMP in tumor cells was located in the cytoplasm with a diffuse or granular pattern; that in the tumor stroma was situated in fibroblasts, leukocytes, and extracellular matrix. Their expression was stronger in CC cases with severe invasion than in CC cases with mild invasion. In contrast, MMP and TIMP were not expressed in any cases of HCC. These results show that intrahepatic bile duct cells may neoexpress or overexpress MMP and TIMP after malignant transformation but that hepatocytes do not, and suggest that MMP and TIMP play an important role in CC cell invasion by degrading extracellular matrix proteins.
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PMID:Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. 867 49

Matrix metalloproteinases (MMPs) have an important role in many biological processes, such as tumor metastasis, wound healing, and inflammation. The regulation of MMPs and their inhibitors is still not known in detail, and the aim of this study was to investigate the effects of dexamethasone on cultured oral benign and malignant cell lines. The expression of MMPs in culture was studied: in four gingival (GF) and one periodontal ligament (PLF) fibroblast cell lines; in six gingival keratinocyte (GK) cell lines; and in UNR (UNR-108, rat osteogenic sarcoma) and SCC (SCC-25, human tongue squamous cell carcinoma) cell lines. In the GFs, PLFs, and UNR cells, only MMP-2 (72 kDa gelatinase) was detected by gelatin zymography, while in most of the GK cell lines only MMP-9 (92 kDa gelatinase) was observed. In confluent SCC cultures, both MMP-2 and MMP-9 were found, while only MMP-2 was seen in rapidly growing SCC cells, demonstrating that cell proliferation influenced gelatinase expression in these cells, but not in the other cell lines studied. Dexamethasone at concentrations of 10(-5) mol/L and 10(-7) mol/L decreased the production of gelatinases in the GFs and PLFs, but not in the GKs, SCC, or UNR cells. The expression of mRNAs for matrix metalloproteinases (MMP-1 [interstitial collagenase] and MMP-2) and their inhibitors (TIMP-1 and TIMP-2) was also studied in the GFs by Northern hybridization. Dexamethasone markedly decreased the amount of MMP-2 mRNA in the GFs. The mRNA level of MMP-1 decreased even more in the same GFs. The mRNA levels for TIMP-1 and TIMP-2 were also decreased by dexamethasone in the GFs. Cell proliferation influenced the degree to which dexamethasone decreased these mRNA levels. The results indicate that glucocorticoids decrease the levels of MMPs and TIMPs in oral fibroblastic cells, whereas they do not appear to affect the production of gelatinases in either normal or malignant oral epithelial cell lines.
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PMID:Effects of dexamethasone and cell proliferation on the expression of matrix metalloproteinases in human mucosal normal and malignant cells. 867 3

72 KDa metalloproteinase (MMP-2) is an enzyme present in neoplastic cells and also in normal fibroblasts. It specifically cleaves type IV collagen, and therefore may play a critical role in tumor invasion and metastasis mechanisms. The aim of the present study was to determine serum levels of MMP-2 in serous ovarian tumors, and compare these with serum levels of CA 125. Ten primary ovarian serous cystadenocarcinomas, 5 borderline tumors, and 10 serous cystadenomas, all treated with primary surgery, were recruited from our series of serous ovarian tumors, and studied. Patients' serum samples were obtained before surgery, and the MMP-2 levels were measured by the substrate capture enzyme-linked immunosorbet assay. The analysis of serum MMP-2, gave values significantly higher in cystadenocarcinomas than in borderline tumors and cystadenomas (one way analysis of variance, P < 0.001); in particular, serum MMP-2 was significantly correlated to the MMP-2 immunostaining of the tumor (Spearman correlation, r = 0.82, and P < 0.001). An arbitrary cutoff of the median value of normal adult female samples (0.22 units) was chosen, and all except for one patient with cystadenocarcinoma was shown to have serum MMP-2 levels above the cutoff value, with 90% sensitivity, 70% specificity, and a 75% positive predictive value (50% of Cohen's Kappa); on the other hand, CA 125 showed 80% sensitivity, and a 73% positive predictive value. The association of serum MMP-2 with CA 125 increased sensitivity to 100% in patients with cystadenocarcinoma, with 70% persisting specificity and a 77% positive predictive value (54% of Cohen's Kappa). Serum MMP-2 levels were found to be significantly increased in patients with cystadenocarcinoma in comparison with borderline tumors and cystadenomas, showing a direct relationship with tissutal MMP-2 expression in serous ovarian tumors. Although our results were preliminary, they clearly suggested that serum MMP-2 may be an interesting diagnostic marker for cystadenocarcinomas.
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PMID:Increased serum 72 KDa metalloproteinase in serous ovarian tumors: comparison with CA 125. 871 54

Matrix metalloproteinases (MMPs), which degrade the components of the extracellular matrix, are key enzymes involved in the tissue remodeling of multicellular organisms. Since MMPs are secreted as inactive zymogens (pro-MMPs), they have to be activated to function. We identified a membrane-type MMP (MT-MMP) that activated proMMP-2 (pro-gelatinase A = 72 kDa type IV pro-collagenase) and described its expression on the invasive tumor cell surface. In this study we further examined the expression and role of MT-MMP in the activation of proMMP-2 during mouse embryogenesis. Northern blotting demonstrated that MT-MMP expression was increased together with that of MMP-2 and its inhibitor gene, TIMP-2, in embryos depending upon the number of days after gestation, and decreased with maturation after birth. In situ hybridization and immunohistochemistry localized MT-MMP mRNA and protein in the cells of ossifying tissues where both MMP-2 and TIMP-2 were expressed. Activated MMP-2 was detected by gelatin zymography in the lysates prepared from the micro dissected tissues that expressed the three genes. The activation rate of proMMP-2 was proportional to the expression of MMP-2 and MT-MMP. These results indicated that proMMP-2 activation through its activator, MT-MMP, is a physiological system used by organisms to initiate tissue remodeling on the cell surface.
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PMID:MT-MMP, the cell surface activator of proMMP-2 (pro-gelatinase A), is expressed with its substrate in mouse tissue during embryogenesis. 874 42

We examined production and tissue localization of matrix metalloproteinase (MMP)-1 (tissue collagenase), MMP-2 (gelatinase A), MMP-3 (stromelysin-1), MMP-9 (gelatinase B), tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in human breast carcinomas. In more than half of the cases, MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 were immunolocalized in carcinoma cells and MMP-2 was on the carcinoma cell membranes as well, whereas MMP-3 was positively stained in less than 15% of the cases. MMP-1 staining in carcinoma cells was significantly higher in scirrhous carcinoma than in other types of carcinoma. MMP-9 expression was remarkably higher in the carcinoma cases with lymphnode metastasis than in the non-metastatic cases. MMP-3 was mainly expressed in T-lymphocytes infiltrated in the tumor stroma. Stromal fibroblasts were positive for all these MMPs except for MMP-3. The TIMP-1 levels released into the culture media by carcinoma tissues were significantly lower than those by fibroadenoma tissues, although there were no significant differences in the levels of MMP-1, MMP-2, MMP-9 and TIMP-2. Gelatin zymographical analyses showed that the activation rate of the zymogen of MMP-2 (proMMP-2) is significantly higher in the more advanced carcinoma group with lymphnode metastasis than in the metastasis-negative and fibroadenoma groups. These data indicate that MMP-1, MMP-2 and MMP-9 are highly expressed in human breast carcinoma tissue and suggest that activation of proMMP-2 may be an indicator of lymphnode metastasis of the breast carcinoma.
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PMID:Production of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human breast carcinomas. 876 24

Enhanced matrix metalloproteinase-2 (MMP-2/72-kd type IV collagenase) action correlates with invasion in neoplasia. MMP-2 is inhibited in vivo by tissue inhibitors of metalloproteinases (TIMPs)-TIMP-1 and, especially, TIMP-2. A synthetic, biotinylated inhibitor specific for activated MMP-2 in solution phase, and immunohistochemistry were used to detect MMP-2 and TIMP-2 expression in cell lines and ovarian tumors and to analyze the surface-binding capacity of the inhibitors, which are potential therapeutic agents. Characterization of novel monoclonal antibodies to MMP-2 and TIMP-2 is described together with immunocytochemical staining of 83 paraffin-embedded ovarian tumors (67 malignant, 7 borderline, 9 benign) and 9 cell lines. Synthetic MMP-2 inhibitor binding under controlled conditions was visualized by immunofluorescence and avidin-biotin complex immunoperoxidase methods in cell lines and cryostat sections of ovarian tumors. MMP-2 and TIMP-2 showed heterogenous immunoreactivity, with enhanced staining on high-grade tumors, specifically at the invasive front and in vascular invasion. TIMP-2 immunoreactivity was maximal in malignant cell cytoplasm and less intense in desmoplastic fibroblasts. One monoclonal antibody to MMP-2 showed membrane immunoreactivity, apically polarized in benign and low-grade tumors but depolarized and strong in 37 of 44 cases of high-grade invasive tumors. Eleven of eighteen ovarian carcinomas and six of nine cell lines showed membrane localization of the synthetic inhibitor. Maximal binding occurred in the ovarian cell line OVCA 432 and the breast cell lines MCF 7 and MDA MB 435, all of which were immunoreactive for MMP-2. Cell lines propagated on type I collagen showed no enhancement in inhibitor binding. This study demonstrates cell surface binding of a synthetic MMP-2 inhibitor and provides new evidence of MMP-2 and TIMP-2 immunoreactivity in ovarian carcinomas and cell lines.
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PMID:Matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression and synthetic matrix metalloproteinase-2 inhibitor binding in ovarian carcinomas and tumor cell lines. 878 Jan 60

The immunohistochemical expression of 72-kDa type IV collagenase [matrix-metalloproteinase (MMP)-21], basement membrane component type IV collagen and proliferation-related antigen Ki 67 were investigated in 43 benign, borderline, and malignant serous tumors of the ovary. The results were compared with the histotypes of ovarian serous tumors and with their clinical behavior. Serum evaluation of MMP-2 was performed in 14 patients with cystadenocarcinoma and the data compared with that of a control group. The basement membrane (BM) was continuous in benign cystadenomas and in some borderline tumors, whereas it was discontinuous or absent in other borderline tumors, in borderline tumors with microinvasion, and cystadenocarcinomas. The percentage of MMP-2- and Ki 67-expressing cells increased from cystadenomas to borderline tumors, being the highest in malignant tumors; a frequent basal disposition of the MMP-2 cytoplasmic granules also was observed in cystadenocarcinomas. Statistical analysis demonstrated that MMP-2 expression was inversely related to BM integrity. Serum MMP-2 values did not differ from that of the control group. Cox regression analysis showed that tumor stage and grade were significant prognostic factors, whereas MMP-2 and Ki 67 immunohistochemical expression added no further significant information to the prognosis. The investigators conclude that the correlation between increasing MMP-2 expression and BM alteration gives support to the hypothesis of a direct role of the metalloproteinase in the process of destructive stromal invasion. MMP-2, type IV collagen, and Ki 67 immunodetection varied according to the histologic classification of ovarian serous tumors. However, neither these factors nor the serum evaluation of MMP-2 appear useful as prognostic predictors in this series.
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PMID:72-kilodalton type IV collagenase, type IV collagen, and Ki 67 antigen in serous tumors or the ovary: a clinicopathologic, immunohistochemical, and Serological study. 878 98

Tumor cells degrade extracellular matrix components (ECM) to invade surrounding tissues. Cancer cells are known to produce various ECM-degrading enzymes including matrix metalloproteinases (MMPs), serine proteinases and cathepsins. Type IV collagen is one of the major components of the basement membrane, and it composes the structural scaffold of these specialized sheets of the ECM. The enzymatic degradation of type IV collagen is initiated by MMPs, in particular MMP-2 (a 72 kDa type IV collagenase) and MMP-9 (a 92 kDa type IV collagenase) which play a key role in cancer invasion and metastasis. In this study, we investigated MMP-2 concentrations and the activity of type IV collagenase in cancer tissue homogenate in 21 cases with head and neck carcinomas and 6 cases with normal mucosa. MMP-2 concentrations did not differ between normal mucosa and tumor tissue without lymphnode metastases. Type IV collagenase activity in normal mucosa was below the detection limit. MMP-2 concentrations had no relation to tumor size, however MMP-2 concentrations in tumor tissue with lymphnode metastases were higher than that in cases without lymphnode metastasis (35.8 +/- 20.5, 20.0 +/- 9.7 ng/mg protein, respectively). However, there was no correlation between MMP-2 concentrations and type IV activity in tumor tissues. These results suggest that MMP-2 plays an important role in tumor invasion and metastasis, so MMP-2 could be a useful biological tumor marker for metastasis and prognosis.
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PMID:[Matrix metalloproteinase-2 concentrations in squamous cell carcinoma of the head and neck and its clinical significance]. 885 35

A hallmark of invasive tumors is their ability to effect degradation of the surrounding extracellular matrix (ECM) by the local production of proteolytic enzymes, such as the matrix metalloproteases (MMPs). In this paper, we demonstrate that the invasion of human gliomas is mediated by a 72 kDa MMP, referred to as MMP-2, and provide further evidence that the activity of MMP-2 is regulated by protein kinase C (PKC). The invasiveness of five human glioma cell lines (A172, U87, U118, U251, U563) was assessed in an in vitro invasion assay and was found to correlate with the level of MMP-2 activity (r2 = 0.95); in contrast, the activity of this 72 kDa metalloprotease was barely detectable in non-invasive control glial cells (non-transformed human astrocytes and oligodendrocytes). Treatment with 1,10-phenanthroline, a metalloprotease inhibitor, or with a synthetic dipeptide, containing a blocking sequence (ala-phe) specific for MMPs, resulted in a > 90% reduction in glioma invasion. Furthermore, this MMP-2 activity could be inhibited by the treatment of tumor cells with calphostin C, a specific inhibitor of PKC. Glioma cell lines treated with calphostin C demonstrated a dose-dependent decrease (IC50 = 30 nM) in tumor invasiveness with a concomitant reduction in the activity of the MMP-2. Conversely, treatment of non-invasive control astrocytes with a PKC activator (phorbol ester) led to a corresponding increase in their invasiveness and metalloprotease activity. These findings support the postulate that MMP-2 activity constitutes an important effector of human glioma invasion and that the regulation of this proteolytic activity can be modulated by PKC.
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PMID:Glioma invasion in vitro: regulation by matrix metalloprotease-2 and protein kinase C. 887 36


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