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)

Hepatocyte growth factor (HGF) plays important roles in tumor development and progression. It is currently thought that the main action of HGF is of a paracrine nature: HGF produced by mesenchymal cells acts on epithelial cells that express its receptor c-MET. In this investigation, we explored the significance of c-MET expression in myofibroblasts, both in culture and in patients with lung adenocarcinoma. We first showed that human myofibroblasts derived from primary lung cancer expressed c-MET mRNA and protein by reverse transcription-polymerase chain reaction and Western blot analysis. Proliferation of myofibroblasts was stimulated in a dose-dependent manner by exogenously added recombinant human HGF whereas it was inhibited in a dose-dependent manner by neutralizing antibody to HGF. The addition of HGF in the culture medium stimulated tyrosine phosphorylation of c-MET. The c-MET protein was immunohistochemically detected in myofibroblasts in the invasive area of lung adenocarcinoma. Finally, the prognostic significance of c-MET expression in stromal myofibroblasts was explored in patients with small-sized lung adenocarcinomas. c-MET-positive myofibroblasts were observed in 69 of 131 cases (53%). A significant relationship between myofibroblast c-MET expression and shortened patient survival was observed in a whole cohort of patients including all pathological stages (two-sided P: = 0.0089 by log-rank test) and in patients with stage IA disease (two-sided P: = 0.0019 by log-rank test). These data suggest that the HGF/c-MET system constitutes an autocrine activation loop in cancer-stromal myofibroblasts. This autocrine system may play a role in invasion and metastasis of lung adenocarcinoma.
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PMID:c-MET expression in myofibroblasts: role in autocrine activation and prognostic significance in lung adenocarcinoma. 1129 May 63

Non-small cell lung cancer is associated with approximately 85% mortality due to its high metastatic potential. Therapeutic efforts have failed to produce a significant improvement in prognosis. In this situation, a better understanding of the key factors of metastasis may be useful for designing new molecular targets of therapy. In order to identify these factors, we compared the expression profiles of two subpopulations of an adenocarcinoma cell line with a high metastatic potential, PC9/f9 and PC9/f14, with the parent cell line, PC9, using a cDNA array. The expression of 15 genes was found to be significantly enhanced or reduced in the highly metastatic subpopulations. The expression of matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor-1 (PAI-1) and interleukin-1 (IL-1 alpha) were upregulated in the highly metastatic subpopulations, while the expression of carcinoembryonic antigen (CEA), caspase-5, Fas ligand, Prk/FNK, cyclin E, cyclin B1, Ki-67, proliferating cell nuclear antigen (PCNA), Smad4, macrophage proinflammatory human chemokine-3 alpha (MIP-3 alpha)/LARC, Met and CD44 were downregulated. Data from the literature suggest that the altered expression of MMP-2, PAI-1, IL-1 alpha, CEA, caspase-5, Fas ligand, Prk/FNK and Smad4 promotes the highly metastatic phenotype. The differential expression of these genes was confirmed by Northern blot analysis, standard reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR. This analysis in subpopulations of a lung cancer cell line indicated that the highly metastatic potential of lung cancer may be induced not by an alteration in the expression of a single gene, but by the accumulation of alterations in the expression of several genes involved in extracellular matrix (ECM) adhesion disruption, ECM degradation, escape from apoptosis, and resistance to transforming growth factor-beta(1) (TGF-beta(1)). Strategies for inhibiting metastasis of pulmonary adenocarcinoma should be designed accordingly.
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PMID:Altered expression of several genes in highly metastatic subpopulations of a human pulmonary adenocarcinoma cell line. 1150 65

The main inhibitory action of p27, a cyclin-dependent kinase inhibitor (CDKI), arises from its binding with the cyclin E/cyclin-dependent kinase 2 (Cdk2) complex that results in G(1)-S arrest. Degradation of p27 is mediated by phosphorylation of Thr-187 of p27, which follows ubiquitination. In this study, we generated two adenoviruses expressing wild-type p27 (ad-p27wt) and mutant p27 (ad-p27mt), with mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC), which was produced with the belief that mutant p27 would bind cyclin E/CDK2 more stably and show more potent antitumor effects. Ad-p27wt and ad-p27mt expressed p27 proteins that were indistinguishable by anti-p27 antibody. A pulse chase experiment showed that p27mt was more resistant to degradation than p27wt. In human lung cancer cell lines, ad-p27mt showed stronger growth inhibition than ad-p27wt. Both types of ad-p27 induced G(1)-S arrest and apoptosis; however, ad-p27mt induced stronger G(1)-S arrest and apoptosis. Intratumoral injection of ad-p27mt induced partial regression of established tumors and inhibited the growth of human lung cancer xenografts more strongly than ad-p27wt. From these results, we conclude that ad-p27mt has the potential to become a novel and powerful gene therapy tool.
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PMID:An adenovirus expressing mutant p27 showed more potent antitumor effects than adenovirus-p27 wild type. 1150 68

The Ah receptor (AhR) is a ligand-dependent transcription factor that positively regulates the expression of the CYP1A1 gene. We investigated the genetic polymorphisms of the AhR gene including the promoter, and examined the link between these polymorphisms, CYP1A1 inducibility and the lung cancer incidence. The AhR promoter region and the 11 exons of 30 subjects were screened. Among the three polymorphisms found, two [(2417)(A/G) ((157)G/A)] have never been described previously. The (1721)(G/A) and (2417)(A/G) are localized in exon 10 and lead to Arg(554)Lys and Met(786)Val substitutions, respectively. The other polymorphism was found in the 5'-untranslated region, resulting in the substitution of a G by an A at position 157 (157)(G/A). To evaluate the frequency of this allelic variant found, a DNA library of a case-control study of lung cancer (162 controls and 177 patients) was studied. There is no significant association between (1721)(G/A), (157)(G/A) and lung cancer: (1721)(G/A) and (157)(G/A) were detected at the same allele frequency of 0.086 and 0.25, respectively in both controls and patients. (2417)(A/G) was found in only one control of 100 (allele frequency 0.005). Statistical analysis did not show any relationship between both (1721)(G/A) and (157)(G/A) polymorphisms found and CYP1A1 inducibility. Considering the rareness of the (2417)(A/G) allelic variant we were not able to evaluate its association with inducibility. In conclusion, none of the polymorphisms were found to play a key role in the CYP1A1 inducibility or in the susceptibility to develop lung cancer.
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PMID:Polymorphisms of human aryl hydrocarbon receptor (AhR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer. 1169 44

The protein product of c-met proto-oncogene, Met, is a tyrosine kinase receptor for the hepatocyte growth factor (HGF). Met receptor is expressed in normal human bronchial epithelium. In comparison, its expression in squamous cell carcinoma (SQCC) of the lung is markedly decreased in a great majority of cases. To understand further the role of Met receptor overexpression in non-small-cell lung carcinoma, we forced-expressed the full-length met cDNA in the NCI-H1264 (H1264) lung carcinoma cell line with low constitutive expression of this receptor. In vitro studies demonstrated that increased Met expression in H1264 cells resulted in strong inhibition of their ability to form soft agar colonies and in marked suppression of tumorigenicity in the subcutaneous tissue of immune-deficient mice. This is despite inconsistent alteration in the proliferation rate on plastic surfaces. Tumor cells explanted from occasional xenograft tumors formed by the Met-overexpressing H1264 cells also demonstrated marked down-regulation of the receptor protein levels as compared to the transplanted cells. The results suggest that constitutive overexpression of Met receptor may negatively regulate the malignancy of certain human lung cancer cells.
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PMID:High expression of Met/hepatocyte growth factor receptor suppresses tumorigenicity in NCI-H1264 lung carcinoma cells. 1179 45

Cancer cells show increased metabolism of both glucose and amino acids, which can be monitored with 18F-2-deoxy-2-fluoro-D-glucose (FDG), a glucose analogue, and 11C-L-methionine (Met), respectively. FDG uptake is higher in fast-growing than in slow-growing tumors. FDG uptake is considered to be a good marker of the grade of malignancy. Several studies have indicated that the degree of FDG uptake in primary lung cancer can be used as a prognostic indicator. Differential diagnosis of lung tumors has been studied extensively with both computed tomography (CT) and positron emission tomography (PET). It has been established that FDG-PET is clinically very useful and that its diagnostic accuracy is higher than that of CT. Detection of lymph node or distant metastases in known cancer patients using a whole-body imaging technique with FDG-PET has become a good indication for PET. FDG uptake may be seen in a variety of tissues due to physiological glucose consumption. Also FDG uptake is not specific for cancer. Various types of active inflammation showed FDG uptake to a certain high level. Understanding of the physiological and benign causes of FDG uptake is important for accurate interpretation of FDG-PET. In monitoring radio/chemotherapy, changes in FDG uptake correlate with the number of viable cancer cells, whereas Met is a marker of proliferation. Reduction of FDG uptake is a sensitive marker of viable tissue, preceding necrotic extension and volumetric shrinkage. FDG-PET is useful for the detection of recurrence and for monitoring the therapeutic response of tumor tissues in various cancers, including those of the lung, colon, and head and neck. Thus, PET, particularly with FDG, is effective in monitoring cancer cell viability, and is clinically very useful for the diagnosis and detection of recurrence of lung and other cancers.
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PMID:From tumor biology to clinical Pet: a review of positron emission tomography (PET) in oncology. 1183 94

Lung cancer is currently the most frequent cause of cancer death in North America. Hepatocyte growth factor (HGF) and its receptor Met are frequently over-expressed in non-small-cell lung carcinomas (NSCLC), but their potential role in tumor progression is not clearly known. To assess the role of HGF/Met signaling in lung carcinomas, we have examined the expression, activation status, and function of Met in NSCLC cell lines (n = 7), established from primary tumors or pleural fluids of cancer patients. We observed Met expression in three NSCLC cell lines, two of which exhibited constitutive tyrosine-phosphorylation of Met, and Met kinase activity. In addition, the observed constitutive activation of Met was sustained under anchorage-independent conditions, and correlated with phosphatidyl inositol 3-kinase-dependent cell survival. Immunoreactive HGF-like protein was secreted by two Met-positive and two Met-negative NSCLC cell lines. However HGF activity, as determined by the ability to induce cell scattering and tyrosine-phosphorylation of Met in reporter cell lines, was detected in conditioned medium from only one Met-negative NSCLC cell line: none of the conditioned media from Met-expressing NSCLC cell lines showed detectable HGF activity. Thus, constitutive activation of Met in NSCLC cell lines may occur at least in part through intracrine, or HGF-independent mechanisms. Interestingly, additional paracrine stimulation with exogenous recombinant HGF was required for DNA synthesis and correlated with increased activation of ERK1/2 in all Met-positive NSCLC cell lines, regardless of the basal activation status of Met. These findings indicate that a medium level of constitutive activation of Met occurs in some NSCLC cell lines, and correlates with survival of detached carcinoma cells; whereas additional paracrine stimulation by recombinant HGF is required for DNA synthesis. Thus constitutive and paracrine activation of Met may provide complementary signals that promote survival and proliferation, respectively, during tumor progression of NSCLC.
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PMID:Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival. 1221 Jul 33

We have previously shown that the toxic pro-oxidant methylselenol is released from selenomethionine (SeMET) by cancer cells transformed with the adenoviral methionine alpha,gamma-lyase (methioninase, MET) gene cloned from Pseudomonas putida. Methylselenol damaged the mitochondria via oxidative stress, and caused cytochrome c release into the cytosol thereby activating caspase enzymes and thereby apoptosis. However, gene therapy strategies are less effective if tumor cells overexpress the antiapoptotic mitochondrial protein bcl-2. In this study, we investigated whether rAdMET/SeMET was effective against bcl-2-overproducing A549 lung cancer cells. We established two clones of the human lung cancer A549 cell line that show moderate and high expression levels of bcl-2, respectively, compared to the parent cell line, which has very low bcl-2 expression. Staurosporine-induced apoptosis was inhibited in the bcl-2-overproducing clones as well as in the parental cell line. In contrast to staurosporine, apoptosis was induced in the bcl-2-overproducing clones as well as the parental cell line by AdMET/SeMET. Apoptosis in the rAdMET-SeMET-treated cells was determined by fragmentation of nuclei, and release of cytochrome c from mitochondria to the cytosol. A strong bystander effect of AdMET/SeMET was observed on A549 cells as well as the bcl-2-overproducing clones. rAdMET/SeMET prodrug gene therapy is therefore a promising novel strategy effective against bcl-2 overexpression, which has blocked other gene therapy strategies.
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PMID:Methioninase gene therapy with selenomethionine induces apoptosis in bcl-2-overproducing lung cancer cells. 1276 89

We have previously demonstrated an enzyme activation prodrug gene therapy strategy using the methionine alpha,gamma-lyase gene (MET) cloned from Pseudomonas putida, in combination with selenomethionine (SeMET) as a prodrug. MET gene transfer via a recombinant adenovirus (Ad-MET) converts the physiologic compound SeMET to highly toxic methylselenol. In this study, we have developed a combination therapy approach using Ad-MET/SeMET gene therapy and doxorubicin (DOX). The combination significantly delayed the growth of H460, an aggressively-growing human lung cancer cell line, in nude mice. H460 cells were injected intra-dermally in nude mice. Tumor-bearing mice were divided into 12 groups [Control (Ctrl), DOX, SeMET, SeMET + DOX, Ad-Ctrl, Ad-Ctrl + SeMET, Ad-Ctrl + DOX, Ad-Ctrl + SeMET + DOX, Ad-MET, Ad-MET + DOX, Ad-MET + SeMET, and Ad-MET + SeMET + DOX]. DOX (2 mg/kg body weight) was given intra-peritoneally twice at 7-day intervals. SeMET (1 microM/mouse) was given by intra-tumor injection everyday, starting the following day after transfection with adenovirus. Tumor growth in the untreated group showed a 10-fold increase in tumor volume after two weeks. In contrast, the increase was only 2.5-fold in the DOX + Ad-MET/SeMET group. The treatment with DOX alone at the low-dose used showed no effect compared to the control group. There was a 5.8-fold increase in tumor volume in mice treated with Ad-MET/SeMET gene therapy alone. The tumor doubling-time was increased to approximately 10 days with the combination therapy of Ad-MET + SeMET + DOX as opposed to 2-3 days in all other treatment groups.
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PMID:Combination efficacy of doxorubicin and adenoviral methioninase gene therapy with prodrug selenomethionine. 1282 Mar 69

Carotenoid supplementation in the treatment of diseases associated with oxidative stress has been recently questioned because of the cell damage and the increased risk of lung cancer in male smokers. Because of the complex role of neutrophils in lung diseases, we investigated whether carotenoid derivatives could affect respiratory burst and apoptosis of human neutrophils purified from peripheral blood. Stimulation of superoxide production was induced by nanomolar and micromolar concentrations of carotenoid cleavage products with aliphatic chains of different length, but not by carotenoids lacking the carbonyl moiety. The stimulatory effect of carotenoid cleavage products was observed in cells activated by phorbol myristate acetate (PMA), while a slight inhibition of superoxide production was noticed with cells activated by the chemotactic tripeptide N-formyl-Met-Leu-Phe (f-MLP). At higher concentrations, carotenoid cleavage products inhibited superoxide production in the presence of both PMA and f-MLP. In the presence of 20 microM carotenoid cleavage products, inhibition of superoxide production was accompanied by DNA fragmentation and increased level of intracellular caspase-3 activity.
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PMID:Carotenoid cleavage products modify respiratory burst and induce apoptosis of human neutrophils. 1294 65


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