Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For the metastasis and invasion of cancer cells, destruction of extracellular matrix is essential. In this process, collagen is broken down by some matrix metalloproteinases. Matrix metalloproteinase 2 (MMP2) is able to cleave type IV collagen, and membrane-type-1-matrix metalloproteinase (MT1-MMP) induces activation of proMMP2. We investigated the expressions of MT1-MMP and MMP2 and their relation to both clinicopathologic parameters and clinical outcome in non-small cell lung carcinomas (NSCLC). Eighty-nine specimens of NSCLC were examined using in situ hybridization and immunohistochemistry. Each metalloproteinase was expressed within the cytoplasm of tumor cells with or without stromal cells in NSCLC. Tumors in which tumor cells strongly stained for MT1-MMP mRNA or protein made up more than 50% of the tumor area were found in 44 and 26% of cases, respectively. The corresponding values for MMP-2 mRNA and protein, were 51 and 26%. Our analysis of clinicopathological findings revealed a significant positive relationship between MT1-MMP mRNA and p-M. The correlation between MMP2 protein-staining status and overall survival rate reached significance in the univariate analysis. However, an association was not demonstrated in the multivariate analysis. The detection of MT1-MMP and MMP2 is likely to be of limited value in informing the prognosis in NSCLC.
Lung Cancer 2002 Mar
PMID:Expression of membrane-type-1-matrix metalloproteinase and metalloproteinase-2 in nonsmall cell lung carcinomas. 1184 98

Homeobox genes regulate sets of genes that determine cellular fates in embryonic morphogenesis and maintenance of adult tissue architecture by regulating cellular motility and cell-cell interactions. Our previous studies showed that a specific member, HOXD3, when overexpressed, upregulates integrin beta3 expression in human erythroleukemia HEL cells and lung cancer A549 cells, and enhances their motility and invasiveness. We performed a microarray study of over 7075 genes to determine the mechanisms underlying the HOXD3-enhanced motility and invasiveness in A549 cells. RT-PCR-based tracking gene analyses highlighted a set of TGF-beta-upregulated genes, which included matrix metalloproteinase-2, syndecan-1, CD44, and TGF-beta-induced 68 kDa protein. Exogenous TGF-beta also caused this pattern of upregulation in A549 cells and enhanced their migratory and invasive activity, confirming the involvement of TGF-beta signaling. However, HOXD3 reduced the expression of TGF-beta-independent genes coding for desmosomal components such as desmoglein, desmoplakin and plakoglobin which are known to suppress tumor invasion and metastasis. These results suggest that HOXD3 enhances the invasive and metastatic potential of cancer cells through the TGF-beta-dependent and -independent pathways.
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PMID:HOXD3 enhances motility and invasiveness through the TGF-beta-dependent and -independent pathways in A549 cells. 1185 Aug 8

Using the intrabronchial orthotopic propagation method, we evaluated the biological characteristics of human adenocarcinoma cell lines in vivo and examined the expressions of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and their related proteins. Nine human lung adenocarcinoma cell lines, including A549, NCI-H23, NCI-H322, NCI-H358, Calu-3, PC-14, LC-2/ad, RERF-LC-KJ and PL16T, were injected into the peripheral bronchi of mice using this method. The mice were sacrificed at 4 and 8 weeks after tumor cell propagation and the lungs and other organs were observed macroscopically and histologically. We classified the adenocarcinoma cell lines, according to their intrapulmonary tumorigenicity, into the following three groups: (A) those that showed a high incidence of intrapulmonary implantation (>50%) (A549 and NCI-H358). A549 showed mediastinal lymph node metastasis and pleural dissemination; (B) those that showed a low incidence of intrapulmonary implantation (PC-14, NCI-H322, NCI-H23, Calu-3, and LC-2/ad); (C) those that showed no tumorigenicity in the lung (RERF-LC-KJ and PL16T). In order to characterize the biological differences between each cell line, we investigated the expressions of MMP-2 and MMP-9 and their related molecules by northern blot analysis. The expressions of MMP-2 and MMP-9 and their activators (membrane-type 1-MMP and urokinase-type plasminogen activator) were thought to be associated with the growth, invasion and metastasis of the human lung adenocarcinoma cell lines examined.
Lung Cancer 2002 Jun
PMID:Intrabronchial orthotopic propagation of human lung adenocarcinoma--characterizations of tumorigenicity, invasion and metastasis. 1200 37

The differential expressions of hundreds of tightly transcriptionally controlled genes in freshly isolated human lung cancers and respective normal lung tissues were analyzed by the cDNA macroarray technique. Three lung cancer patients received pre-operative chemotherapy with cisplatin containing regimens. After chemotherapy, these patients underwent surgery, and poly (A)-RNA expressions of 588 genes in the samples prepared from the lung cancer and normal lung tissues were compared. These expressions of the 588 genes were demonstrated by spotting onto a filter. Histogram analysis of gene expression revealed the tumors to show commonly up-regulated expression of angiogenesis and invasion related genes and adhesion molecules such as fibroblast growth factor 3 (FGFR3), matrix metalloproteinase (MMP)15, 16 and 10, integrin beta 4, integrin alpha 9, endonexin, and several types of collagens. Thus, post-chemotherapeutic tissues from lung cancer parents are characterized by remarkable up-regulation of molecules related to angiogenesis, invasion and adhesion. Tree view showed close clustering of angiogenesis related genes. Furthermore, when the angiogenesis related genes were selected and clustered, they were categorized into three groups depending upon gene expression profiles. These results suggest that angiogenesis related molecules are suitable candidates for target-based therapeutics and angiogenesis inhibitors are expected to be effective in lung cancer patients pretreated with chemotherapy.
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PMID:Up-regulated gene expression of angiogenesis factors in post-chemotherapeutic lung cancer tissues determined by cDNA macroarray. 1206 99

Our previous data showed that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit matrix metalloproteinase-2 (MMP-2) expression via repression of gene transcription in lung cancer cells. In this study, we investigate the molecular mechanism by which NSAIDs inhibit MMP-2. Promoter deletion and mutation analysis indicate that NSAIDs act via the Sp1 transcription factor binding site located between -91 and -84 in the MMP-2 promoter to suppress gene expression. Electrophoretic mobility shift assays show that Sp1 and Sp3 proteins constitutively bind to this consensus sequence and overexpression of Sp1 may enhance MMP-2 expression. NSAID treatment reduces Sp1 DNA binding activity and phosphorylation and attenuates MMP-2 expression. We also investigate the signaling pathway that mediates the effect of NSAIDs. Our results suggest that ERKs are involved in this process. First, NSAIDs suppress basal and serum-stimulated ERK activity. Second, a MEK inhibitor PD98059 inhibits MMP-2 promoter activity and Sp1 phosphorylation. Third, overexpression of constitutively active MEK1 stimulates Sp1 phosphorylation and MMP-2 promoter activity and antagonizes the inhibition of NSAIDs. Collectively, our data suggest that NSAIDs inhibit MMP-2 by blocking ERK/Sp1-mediated transcription.
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PMID:Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription. 1208 91

Although both hepatocyte growth factor (HGF) and interleukin (IL)-6 play important roles in invasion of cancer cells, interaction between these two critical factors has not been well elucidated. In the present study we demonstrated a two-way interaction between HGF and IL-6 in in vitro invasion of a lung cancer cell line. A549 lung adenocarcinoma cells were stimulated with IL-6, and this treatment induced an upregulation of c-Met/HGF receptor mRNA expression in the cells. In addition, IL-6 enhanced the HGF-induced in vitro cell invasion. This effect was abolished by pretreatment of the cells with either anti-IL-6 neutralizing antibody or with anti-c-Met/HGF receptor blocking antibody. We also found that HGF upregulated the expression of IL-6 receptor mRNA in the same cell line, and that this upregulation enhanced the IL-6-induced cell invasion. Finally, costimulation with HGF and IL-6 showed an additive effect on invasion, and this effect was mediated by production of matrix metalloproteinase (MMP)-2 and MMP-9. These results suggest that HGF and IL-6 upregulate each other's receptors, and thus would cooperatively enhance tissue invasion. They also suggest an "autocrine circuit" among cytokines and growth factors in certain cancer cells which functions to accelerate their biologic activities such as metastatic property.
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PMID:A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell line. 1215 14

Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness. A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development. Such new agents include antibody epithelial growth factor receptor (EGFR) inhibitors (eg, the monoclonal antibodies trastuzumab [Herceptin] and cetuximab [IMC-C225, Erbitux]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors), vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF ligand and small-molecule tyrosine kinase), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-alpha). A number of these agents have entered advanced-phase clinical investigation. It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment, including maintenance therapy. It is even possible that these new biologic therapies will be used together as rational combinations (based on pathologic diagnosis) for advanced non-small-cell lung cancer.
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PMID:Targeted therapy in non-small-cell lung cancer. 1237 97

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to exert anti-angiogenic and anti-metastatic activity both in vitro and in vivo. Block of angiogenesis and metastasis by NSAIDs has been found to be mediated partly via suppression of matrix metalloproteinase (MMP) activity. However, the molecular mechanism of this inhibitory action has not been well defined. Recent works demonstrated that a membrane-anchored MMP inhibitor RECK may potently suppress MMP-2 and -9 activity to inhibit angiogenesis and metastasis in vitro and in vivo. In this study, we test the possibility that NSAIDs may up-regulate RECK to inhibit MMP activity. RT-PCR analyses showed that NS398 and aspirin up-regulated RECK mRNA level in CL-1 human lung cancer cells. Additionally, NSAIDs increased RECK protein level as detected by immunoblotting. Since RECK is a membrane-anchored glycoprotein, we also performed immunofluorescent staining to assess the expression of RECK on cell surface. Our results showed that fluorescent intensity of RECK was obviously increased after NSAID treatment. Moreover, induction of RECK by NSAIDs was associated with reduction of MMP-2 activity. We also found that NSAID-activated RECK expression might not be mediated via inhibition of cyclo-oxygenases (COXs) because addition of prostaglandin E(2) (PGE(2)) could not counteract the effect of NSAIDs and overexpression of COX-2 could not down-regulate RECK. Taken together, our results suggest that induction of RECK expression may be one of the mechanisms by which NSAIDs suppress MMP activity to block angiogenesis and metastasis.
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PMID:Induction of RECK by nonsteroidal anti-inflammatory drugs in lung cancer cells. 1244 98

In this study, we investigated activity of matrix metalloproteinase (MMP) of lung cancer by newly developed film in situ zymography (FIZ) stamp method, which allows visual localization of gelatinolytic activity within the cut surface of a tumor. We performed FIZ stamp method and conventional gelatin zymography in 39 resected specimen of lung cancer. The degree of gelatinolytic activity was scored (FIZ score) and correlated with the clinicopathological factors of the tumor. FIZ score of normal lung was very low. Lung cancer tissue had consistently higher FIZ score than the matched normal lung tissue. There were statistically significant differences in the FIZ score according to the pathological stage (P = 0.0015), nodal status (P = 0.0007) and lymphatic invasion (P = 0.0004). Direct correlation was observed between the FIZ score and MMP-2 activity (rho = 0.568, P = 0.0030) as quantitated using conventional gelatin zymography. MMP-2 may play an important role in the lymphatic invasion of lung cancer. FIZ stamp method may be a simple and useful diagnostic aid for the presence of cancer cells in the resected specimen.
Lung Cancer 2003 Feb
PMID:Gelatinolytic activity of matrix metalloproteinase in lung cancer studied using film in situ zymography stamp method. 1258 63

Histone deacetylase (HDAC) inhibitors are known to exert antimetastatic and antiangiogenic activity in vitro and in vivo. RECK is a membrane-anchored glycoprotein that negatively regulates matrix metalloproteinases (MMPs) and inhibits tumor metastasis and angiogenesis. In this study, we test the possibility that HDAC inhibitor may increase RECK expression to inhibit MMP activation and cancer cell invasion. Our results showed that trichostatin A (TSA) up-regulated RECK via transcriptional activation in CL-1 human lung cancer cells. Flow cytometric analysis demonstrated that RECK protein on cell surface was increased after treatment of TSA. Moreover, up-regulation of RECK expression by TSA attenuated MMP-2 activity. To explore whether HDAC inhibitor-induced inhibition of MMP-2 activation is indeed mediated via RECK, we used small interference RNA (siRNA) to block RECK expression and found that inhibition of RECK by siRNA abolished the inhibitory effect of TSA on MMP-2 activation. In addition, TSA suppressed the invasive ability of CL-1 cells. Taken together, this study reveals a novel mechanism by which HDAC inhibitors suppress tumor invasion and provides a new strategy for cancer therapy.
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PMID:Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. 1281 Jun 30


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