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)

The effect of the matrix metalloproteinase inhibitor batimastat was evaluated in two human colorectal cancer metastasis models involving: (a) the liver-invasive tumor C170HM2 and (b) the lung-invasive tumor AP5LV, both of which have been shown to express the M(r) 72,000 type IV collagenase. Batimastat at concentrations between 0.01 and 3.0 micrograms/ml had no direct cytotoxic effects on the in vitro growth of the cell lines. In the liver-invasive tumor model, batimastat administered i.p. from day 10 to termination of the therapy (day 39) at 40 mg/kg reduced both the mean number of liver tumors (35% of vehicle-treated control; P < 0.05) and the cross-sectional area of the tumors (43% of vehicle-treated control; P < 0.05). In the lung-invasive tumor model, batimastat administered daily (40 mg/kg i.p.) significantly reduced tumor weight within the lung (72% of vehicle-treated control; P < 0.05) but did not significantly affect nodule number. In the latter model, in which the take rate was unaffected, tumor cells were introduced into the lateral tail vein, and lung localization may have been a physical phenomenon not involving invasion. In the former model, tumor cells were introduced directly into the peritoneal cavity, and from there the cells adhered to and invaded the liver capsule. Because the take rate is significantly reduced, it may be that the matrix metalloproteinases are involved in this process. Batimastat may be a therapeutic modality for the treatment of colorectal cancer metastasis.
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PMID:Inhibition of organ invasion by the matrix metalloproteinase inhibitor batimastat (BB-94) in two human colon carcinoma metastasis models. 762 72

Gelatinase A, a matrix metalloproteinase, is frequently associated with human solid tumors, and its secretion and activation in the tumor milieu is considered important in the process of angiogenesis, invasion, and metastasis. Consequently, metalloproteinase inhibitors may be of value in the therapy of cancer as well as other disease states involving tissue remodeling and release of biologically active peptide/protein by proteolytic cleavage. Here we describe the development of a rapid screening assay for in vivo activity of peptidomimetic inhibitors of gelatinase A that involves assessment of inhibition of an enzyme-substrate reaction in a circumscribed body compartment, the mouse pleural cavity. As examples of the utility of this assay, in vivo activity of the aryl sulfonamide, sulfamyl urea, morpholino and carboxylic acid functionality at the P3' position of a series of hydroxamic acid inhibitors was examined after administration both intraperitoneally (ip) (to approximate systemic administration) and orally. For up to 2 h after ip administration, all inhibitors tested showed marked activity (> 90% inhibition) at 17 mumol/kg (approximately 10 mg/kg). This activity declined in a dose-responsive manner to insignificant levels at 0.67 mumol/kg (approximately 0.4 mg/kg). Aryl sulfonamides showed significant inhibition (> 50%) for up to 7 h after administration. A higher dosage (136 mumol/kg, approximately 80 mg/kg) was required to reveal oral activity, which was observed only with morpholino compounds (> 50% inhibition). Thus, the model described may be of value in the identification of orally active gelatinase A inhibitors.
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PMID:An in vivo model for screening peptidomimetic inhibitors of gelatinase A. 762 28

The matrix metalloproteinases (MMPs) have been associated with tissue remodeling in many normal and pathological processes, and in particular are thought to be critical for tumor invasion and metastasis. MMP overexpression has been correlated with the stage of progression in several tumor types. Because of the aberrant nature of tumor cells, it has been assumed that the tumor cells themselves are responsible for this abnormal MMP production. However, recent in situ hybridization experiments have determined that, while some members of the MMP family are expressed within neoplastic cells, many are found in normal stromal components immediately adjacent to the tumor tissue. In this review, we address the potential roles of both tumor and stromal MMPs in tumor progression. Also, using MMP expression as a point of reference, we discuss some of the potential mechanisms involved in tumor/host interactions.
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PMID:Tumor and stromal expression of matrix metalloproteinases and their role in tumor progression. 765 16

Matrix metalloproteinases are believed to play an important role in tumor invasion and metastasis. To examine the expression of the stromelysin 3 (ST3) gene, a new member of the matrix metalloproteinase gene family, 111 head and neck squamous cell carcinomas and 21 metastatic lymph nodes were analyzed by Northern blot. ST3 gene expression was observed in 106 carcinomas and 19 metastatic nodes, but in only 2 of 60 samples of corresponding normal tissue tested in parallel. ST3 RNA, by in situ hybridization, and ST3 protein, by immunohistochemical analysis, were specifically detected in fibroblastic cells immediately surrounding invasive cancer cells. This fibroblastic expression of the ST3 gene is characteristic among the matrix metalloproteinase genes known to be overexpressed in head and neck carcinomas, since stromelysin 2 transcripts were specifically detected in neoplastic cells, and type I collagenase transcripts in both neoplastic cells and stromal fibroblasts. Furthermore, there was a highly significant positive correlation (P < 0.0001) between ST3 RNA levels and local invasiveness by the cancer cells, suggesting that enhanced expression of the ST3 gene may contribute to the neoplastic phenotype in head and neck carcinomas.
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PMID:Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas. 767 79

The 72-kDa Type IV collagenase (T4C) is a matrix metalloproteinase, the expression of which may be important in normal basement membrane metabolism. The production of T4C by malignant cells has been linked to their invasive and metastatic potential in several tumor systems. The pattern of T4C immunoreactivity was assessed in formalin-fixed, paraffin-embedded prostatic tissue using polyclonal, monospecific antibodies. Basal cells in normal and hyperplastic epithelium demonstrated slight to moderate cytoplasmic immunoreactivity, while secretory epithelial cells showed generally weaker immunostaining. In 35 of 35 cases of primary adenocarcinoma and five of five cases of metastatic adenocarcinoma in lymph nodes, the majority of malignant cells showed strong immunoreactivity. Similar strong immunostaining was also seen in foci of prostatic intraepithelial neoplasia. The high level of expression of T4C in prostatic adenocarcinoma and its metastases suggests this metalloproteinase may play a role in determining the invasive and metastatic properties of this tumor. The enhanced immunoreactivity in prostatic intraepithelial neoplasia suggests the induction of T4C may be an early event in the development of the invasive phenotype. The expression of T4C in benign epithelial cells may be a manifestation of its putative physiological role in basement membrane metabolism.
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PMID:Immunohistochemical analysis of type IV collagenase expression in prostatic hyperplasia and adenocarcinoma. 767 36

Matrilysin is a member of the matrix metalloproteinase gene family, which is believed to play an important role in tumor invasion and metastasis. We examined the effects of over- and under-expression of matrilysin on the ability of colon cancer cells to migrate across an artificial membrane in vitro. Introduction of matrilysin caused colon cancer cells to become more invasive as assessed by an in vitro invasion assay. In contrast, expression of matrilysin was down-regulated by all trans-retinoic acid or by introduction of anti-sense matrilysin in BM314 colon cancer cells. This down-regulation caused these cells to become less invasive. We demonstrated a correlation between matrilysin level and the invasive potential of human colon cancer cells, implying an important role for matrilysin in the control of tumor invasion in vitro.
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PMID:Suppression of matrilysin inhibits colon cancer cell invasion in vitro. 770 51

An Ets-related E1A-F has been characterized as an enhancer-binding protein for the adenovirus E1A gene. Here we show, in transient expression assays, that E1A-F can activate three different subclasses of the matrix metalloproteinase gene promoters. Expressions of the chloramphenicol acetyltransferase (CAT) reporter gene under the control of stromelysin, type I collagenase and 92 kD type IV collagenase promoters were increased approximately 10- to 20-fold by co-transfection with the E1A-F expression vector. Activation levels were as much high as those obtained by exogenous expression of AP-1 transcription factor. These results suggest that E1A-F positively regulates transcriptions from matrix metalloproteinase genes that are associated with invasion and metastasis of tumor cells.
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PMID:Ets-related protein E1A-F can activate three different matrix metalloproteinase gene promoters. 773

We have examined the effect that cell shape has on production of the 92-kDa gelatinase B, an enzyme of the matrix metalloproteinase family thought to contribute to the invasiveness of both normal and malignant cells. Using the agent poly(HEMA) and a human melanoma cell line that constitutively produces both the 72- and 92-kDa gelatinases, we have found that alteration in cell shape, that is, a change in cell "roundness," resulted in a specific loss of the constitutive production of the 92-kDa gelatinase B. To examine this phenomenon further, cells were treated with an inhibitor of actin polymerization, cytochalasin D. This treatment also resulted in a loss of 92-kDa gelatinase B production, provided the cells were treated with drug from the out-set of the experiment. If the cells were allowed to attach and spread prior to drug exposure, no loss of 92-kDa gelatinase B production was observed. Similar to the poly (HEMA) results, cytochalasin D had little effect on production of the 72-kDa gelatinase A. Treatment with the tubulin polymerization inhibitor colchicine had no effect on 92-kDa gelatinase B production, nor did growth of the cells as three-dimensional tumor spheroids, although an alteration in cell morphology was observed in both instances. This phenomenon was studied in another system, namely, HL-60 cells, which were induced to differentiate into macrophage-like cells in response to TPA treatment and consequently produce the 92-kDa gelatinase B. HL-60 cells treated with TPA and cytochalasin D failed to produce the 92-kDa gelatinase B. These results suggest that the 92-kDa gelatinase B can be regulated by alterations in cell shape but more specifically, by alterations in the organization of the actin cytoskeleton. Furthermore, the mechanism responsible for cell shape/actin cytoskeletal down-regulation of the 92-kDa gelatinase B may be common to many cell types competent to produce this enzymatic activity.
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PMID:Constitutive production of 92-kDa gelatinase B can be suppressed by alterations in cell shape. 779 86

We identified a new matrix metalloproteinase (membrane type matrix metalloproteinase (MT-MMP)) that has a potential transmembrane (TM) domain at the C terminus and reported its expression on the surface of invasive tumor cells. The expression of MT-MMP induced specific activation of 72-kDa pro-gelatinase A (Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) Nature 370, 61-65). Thus, MT-MMP on the cell surface is thought to play an important role in various physiological and pathological processes accompanying tissue remodeling. In this study, we demonstrated that the potential TM domain deduced from the amino acid sequence functions as a membrane linker when it is fused to a secretory protein, tissue inhibitor of matrix metalloproteinases-1. The pro-gelatinase A activation function of MT-MMP was abolished by truncation of the TM domain and recovered by fusing the MT-MMP mutant with the TM domain of interleukin 2 receptor alpha-chain. The truncated MT-MMP was released from the cells into the medium and detected as processed or modified forms. In spite of the deletion of the TM domain some portions of the mutant MT-MMP were still retained on the surface of cells. Thus, MT-MMP has an additional device to keep it on the cell surface. The TM domain however, plays an essential role in the pro-gelatinase A activation function of MT-MMP, probably regulating its fine orientation or the localization that is necessary to interact with substrate.
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PMID:The C-terminal region of membrane type matrix metalloproteinase is a functional transmembrane domain required for pro-gelatinase A activation. 782 14

Several recent investigations have demonstrated that matrix metalloproteinase-2 (MMP-2) binds to the cell surface and undergoes zymogen activation via a plasma membrane-associated activity. The purpose of this study was to determine if association of MMP-2 with the plasma membrane also modulates the catalytic efficiency of the active enzyme. Using density gradient centrifugation, we isolated the plasma membrane fractions of two ovarian adenocarcinoma cell lines, DOV 13 and OVCA' 432, previously described either to express MMP-2 or to express no gelatinolytic metalloproteinases, respectively. While DOV 13 cells contained plasma membrane-associated MMP-2 and OVCA 432 did not, both cell types were able to bind exogenous MMP-2. Furthermore, plasma membrane fractions from these cells significantly enhanced the rate of cleavage of [14C]gelatin I substrate by both MMP-2 tissue inhibitor of metalloproteinases-2 (TIMP-2) complex (2.5-8-fold) and TIMP-2-free MMP-2 (5.9-fold). This stimulatory activity was dose-dependent, soluble in Triton X-100, and abolished by trypsin treatment of the membranes, but was stable to heat treatment. Plasma membrane stimulation of MMP-2 resulted in a 3.8-4.6-fold increase in the catalytic efficiency of gelatinolysis. These data suggest that, in addition to promoting zymogen activation, cell surface binding of MMP-2 may regulate enzyme activity by increasing the rate of substrate cleavage. Via this mechanism, tumor cell types that do not express MMPs (such as OVCA 432) nevertheless may be able to utilize exogenous MMP-2 to mediate proteolysis associated with invasion and metastasis.
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PMID:A plasma membrane-associated component of ovarian adenocarcinoma cells enhances the catalytic efficiency of matrix metalloproteinase-2. 783 20


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