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Technology in Cancer Research &... Aug 2004Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular...
Macromolecular contrast medium-enhanced magnetic resonance imaging was applied to monitor the effect of matrix metalloprotease (MMP) inhibition on microvascular characteristics of human breast cancers implanted in athymic rats. Twice-daily intraperitoneal administration of Prinomastat over 1.5 days induced significant declines in MRI-assayed microvascular permeabilities (p<0.05); but this leak suppression effect had extinguished by the 10(th) day of MMP treatment using the same dose and time schedule. Results demonstrate that Prinomastat produces a rapid but transient decrease in tumor vascular permeability. Contrast-enhanced MRI using macromolecular contrast medium may prove useful as a biomarker for the dynamic MMP biological effect in cancers.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Capillary Permeability; Cell Division; Cell Line, Tumor; Contrast Media; Enzyme Inhibitors; Female; Homozygote; Humans; Magnetic Resonance Imaging; Matrix Metalloproteinase Inhibitors; Microcirculation; Neoplasm Transplantation; Neoplasms; Organic Chemicals; Rats; Rats, Nude; Statistics as Topic; Time Factors
PubMed: 15270589
DOI: 10.1177/153303460400300408 -
American Journal of Physiology. Lung... Aug 2004Murine Mycoplasma pulmonis infection induces chronic lung and airway inflammation accompanied by profound and persistent microvascular remodeling in tracheobronchial...
Murine Mycoplasma pulmonis infection induces chronic lung and airway inflammation accompanied by profound and persistent microvascular remodeling in tracheobronchial mucosa. Because matrix metalloproteinase (MMP)-2 and -9 are important for angiogenesis associated with placental and long bone development and skin cancer, we hypothesized that they contribute to microvascular remodeling in airways infected with M. pulmonis. To test this hypothesis, we compared microvascular changes in airways after M. pulmonis infection of wild-type FVB/N mice with those of MMP-9(-/-) and MMP-2(-/-)/MMP-9(-/-) double-null mice and mice treated with the broad-spectrum MMP inhibitor AG3340 (Prinomastat). Using zymography and immunohistochemistry, we find that MMP-2 and MMP-9 rise strikingly in lungs and airways of infected wild-type FVB/N and C57BL/6 mice, with no zymographic activity or immunoreactivity in MMP-2(-/-)/MMP-9(-/-) animals. However, microvascular remodeling as assessed by Lycopersicon esculentum lectin staining of whole-mounted tracheae is as severe in infected MMP-9(-/-), MMP-2(-/-)/MMP-9(-/-) and AG3340-treated mice as in wild-type mice. Furthermore, all groups of infected mice develop similar inflammatory infiltrates and exhibit similar overall disease severity as indicated by decrease in body weight and increase in lung weight. Uninfected wild-type tracheae show negligible MMP-2 immunoreactivity, with scant MMP-9 immunoreactivity in and around growing cartilage. By contrast, MMP-2 appears in epithelial cells of infected, wild-type tracheae, and MMP-9 localizes to a large population of infiltrating leukocytes. We conclude that despite major increases in expression, MMP-2 and MMP-9 are not essential for microvascular remodeling in M. pulmonis-induced chronic airway inflammation.
Topics: Animals; Epithelial Cells; Gene Expression Regulation, Enzymologic; Immunohistochemistry; Leukocytes; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neovascularization, Pathologic; Pneumonia, Mycoplasma; Pulmonary Circulation; Trachea
PubMed: 15075248
DOI: 10.1152/ajplung.00404.2003 -
Annales de Biologie Clinique 2003Matrix metalloproteinases (MMPs) play a key role in the physiology of connective tissue development, morphogenesis and wound healing, but their unregulated activity has... (Comparative Study)
Comparative Study Review
Matrix metalloproteinases (MMPs) play a key role in the physiology of connective tissue development, morphogenesis and wound healing, but their unregulated activity has been implicated in numerous disease processes including arthritis, tumor cell metastasis and atherosclerosis. MMP family consists of at least 20 members; MMPs are produced by the different cell types (vascular smooth muscle cells, monocytes, endothelial cells) involved in the atheromatous plaque formation and participate to extracellular matrix remodelling and cell infiltration or migration. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention to modify vascular pathology, by restoring the MMP/TIMP physiological equilibrium. This review highlights the structures of MMPs and their physiological inhibitors, the Tissue Inhibitors of MMPs (TIMPs), and describes the current developments in pharmacological MMP inhibition.
Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Aortic Diseases; Arteriosclerosis; Case-Control Studies; Clinical Trials as Topic; Coronary Artery Disease; Doxycycline; Humans; Hydroxamic Acids; Hyperlipidemias; Hypolipidemic Agents; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Metalloendopeptidases; Organic Chemicals; Phenylalanine; Polymorphism, Genetic; Prospective Studies; Rats; Risk Factors; Thiophenes; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-3; Tissue Inhibitor of Metalloproteinases
PubMed: 12702469
DOI: No ID Found -
American Journal of Physiology. Lung... Mar 2003High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix...
High-volume mechanical ventilation leads to ventilator-induced lung injury. This type of lung injury is accompanied by an increased release and activation of matrix metalloproteinases (MMPs). To investigate the mechanism leading to the increased MMP release, we systematically studied the effect of mechanical stretch on human microvascular endothelial cells isolated from the lung. We exposed cells grown on collagen 1 BioFlex plates to sinusoidal cyclic stretch at 0.5 Hz using the Flexercell system with 17-18% elongation of cells. After 4 days of cell stretching, conditioned media and cell lysate were collected and analyzed by gelatin, casein, and reverse zymograms as well as Western blotting. RT-PCR of mRNA extracted from stretched cells was performed. Our results show that 1) cyclic stretch led to increased release and activation of MMP-2 and MMP-1; 2) the activation of MMP-2 was accompanied by an increase in membrane type-1 MMP (MT1-MMP) and inhibited by a hydroxamic acid-derived inhibitor of MMPs (Prinomastat, AG3340); and 3) the MMP-2 release and activation were preceded by an increase in production of extracellular MMP inducer (EMMPRIN). These results suggest that cyclic mechanical stretch leads to MMP-2 activation through an MT1-MMP mechanism. EMMPRIN may play an important role in the release and activation of MMPs during lung injury.
Topics: Antigens, CD; Antigens, Neoplasm; Antineoplastic Agents; Basigin; Blotting, Western; Cell Line; Culture Media, Conditioned; Endothelium, Vascular; Enzyme Activation; Enzyme Induction; Enzyme Inhibitors; Humans; Lung; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases, Membrane-Associated; Membrane Glycoproteins; Metalloendopeptidases; Organic Chemicals; Periodicity; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Stress, Mechanical; Tissue Inhibitor of Metalloproteinase-2
PubMed: 12456388
DOI: 10.1152/ajplung.00290.2002 -
Journal of Virology Mar 2002The release of neurotoxins by activated brain macrophages or microglia is one mechanism proposed to contribute to the development of neurological disease following...
The release of neurotoxins by activated brain macrophages or microglia is one mechanism proposed to contribute to the development of neurological disease following infection by lentiviruses, including feline immunodeficiency virus (FIV). Since molecular diversity in the lentiviral envelope gene influences the expression of host molecules implicated in neuronal injury, the role of the envelope sequence in FIV neuropathogenesis was investigated by using the neurovirulent FIV strain V1CSF, the nonneurovirulent strain Petaluma, and a chimera (FIVCh) containing the V1CSF envelope gene in a Petaluma background. All three viruses replicated in primary feline macrophages with equal efficiency, but conditioned medium from V1CSF- or FIVCh-infected cells was significantly more neurotoxic than medium from Petaluma-infected cultures (P < 0.001) and could be attenuated in a dose-dependent manner by treatment with either the matrix metalloproteinase (MMP) inhibitor prinomastat (PMT) or function-blocking antibodies to MMP-2. Although FIV sequences were detectable by PCR in brain tissue from neonatal cats infected with each of the viral strains, immunohistochemistry revealed increased astrogliosis and macrophage activation in the brains of V1CSF- and FIVCh-infected cats relative to the other groups, together with elevated markers of neuronal stress that included morphological changes and increased c-fos immunoreactivity. Similarly, MMP-2, but not MMP-9, mRNA and protein expression was increased in brain tissues of V1CSF- and FIVCh-infected cats relative to Petaluma-infected animals (P < 0.01). Infection with V1CSF or FIVCh was also associated with greater CD4(+) cell depletion (P < 0.001) and neurodevelopmental delays (P < 0.005), than in Petaluma-infected animals; these deficits improved following PMT therapy. These findings indicated that diversity in the envelope gene sequence influenced the neurovirulence exhibited by FIV both in vitro and in vivo, possibly through a mechanism involving the differential induction of MMP-2.
Topics: Animals; Animals, Newborn; Brain; Cats; Central Nervous System Viral Diseases; Female; Gene Expression Regulation, Viral; Genes, env; Humans; Immunodeficiency Virus, Feline; Infant, Newborn; Lentivirus Infections; Macrophages; Matrix Metalloproteinases; Mice; Neurons; Pregnancy; Tumor Cells, Cultured; Viral Envelope Proteins; Virulence
PubMed: 11861828
DOI: 10.1128/jvi.76.6.2622-2633.2002 -
The Journal of Biological Chemistry Mar 2002Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases,...
Processing of integrin alpha(v) subunit by membrane type 1 matrix metalloproteinase stimulates migration of breast carcinoma cells on vitronectin and enhances tyrosine phosphorylation of focal adhesion kinase.
Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases, MT1-MMP directly processes a single chain precursor of alpha(v) integrin subunit (pro-alpha(v)) into the heavy and light alpha-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing alpha(v)beta(3) integrin with either the wild type or mutant MT1-MMP in a variety of migration and adhesion tests. Specific inhibitors of proprotein convertases and MMP were employed in our cell system to attenuate the individual pathways of pro-alpha(v) maturation. We present evidence that MT1-MMP cleavage of pro-alpha(v) in the cells did not affect RGD-ligand binding of the resulting alpha(v)beta(3) integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and alpha(v)beta(3) integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of alpha(v)beta(3) integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and alpha(v)beta(3) integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. Regulation of integrin maturation and functionality may be an important role of MT1-MMP in tumor cells.
Topics: Antineoplastic Agents; Binding Sites; Blotting, Western; Cell Adhesion; Cell Movement; Disulfides; Dose-Response Relationship, Drug; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Ligands; Matrix Metalloproteinase 1; Oligopeptides; Organic Chemicals; Phosphorylation; Precipitin Tests; Protein Binding; Protein-Tyrosine Kinases; Receptors, Vitronectin; Time Factors; Transfection; Tumor Cells, Cultured; Tyrosine; Vitronectin
PubMed: 11724803
DOI: 10.1074/jbc.M110269200 -
The International Journal of Biological... 1999Matrix metalloproteases (MMPs) are a family of structurally related enzymes that are capable of degrading proteins of the extracellular matrix. These enzymes play a role... (Review)
Review
Matrix metalloproteases (MMPs) are a family of structurally related enzymes that are capable of degrading proteins of the extracellular matrix. These enzymes play a role in tissue remodelling associated with both physiological and pathogenic processes. A high expression of MMPs is associated with cancer malignancy: it is related to the tumor's ability to metastasize and to the process of angiogenesis. Treatment with MMP inhibitors alone or in combination with cytotoxic therapy is an interesting novel approach to control tumor progression. The expected mechanism of action of these compounds and the difference in side effects compared to cytotoxic drugs make the definition of endpoints and the assessment of response difficult. Furthermore, it is not yet clear whether tumor vascularization or, more specifically, MMP expression/activation should be a criterion of eligibility for this kind of treatment. This review provides an overview of the characteristics of MMPs and their role in tumor progression, metastasis and angiogenesis. Preclinical and clinical studies with synthetic MMP inhibitors are described. The presence of MMPs in biological fluids of patients and their use in prognostic evaluation and in determining the efficacy of treatment with MMP inhibitors is discussed.
Topics: Animals; Antineoplastic Agents; Azepines; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Organic Chemicals; Phenylalanine; Protease Inhibitors; Thiophenes
PubMed: 10669951
DOI: 10.1177/172460089901400406