UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-small cell lung cancer is the most common cause of cancer-related death in North America and Europe. Despite improvements in the diagnosis and treatment of the disease the prognosis remains poor, the overall 5-year survival being 4-14%. An increased understanding of the molecular biology of the disease may identify novel targets for drug development. We evaluated epidermal growth factor receptor (EGFR), HER-2/neu, matrix metalloproteinase (MMP)-2, MMP-9, p53 and bcl-2 expression and microvessel density (MVD) in patients who underwent surgery with curative intent in our department between 1991 and 1996. Co-expression of EGFR/MMP-9, MVD and bcl-2 were found to be independent prognostic variables, which allowed prediction of patient outcome independent of surgical stage. Other prognostic factors identified in our series were gender, surgical stage, platelet count, extent of necrosis, the hypoxia marker carbonic anhydrase-9 and beta-catenin. In collaboration with groups in Oxford and Greece, we were also able to establish the angiogenic growth factors vascular endothelial growth factor and platelet-derived endothelial growth factor as prognostic variables. The inter-relationships between these factors are currently being examined in an expanded patient series. Through this work we hope to be able to construct an integrated biological prognostic model which can be tested in prospective studies. This work has identified several potential targets for novel therapeutic agents currently in development.
Lung Cancer 2001 Dec
PMID:Towards a biological staging model for operable non-small cell lung cancer. 1172 Jul 47

Recent studies show that up-regulation of cyclooxygenase-2 (COX-2) in human cancer cells induces activation of matrix metalloproteinases (MMPs) and increase of metastatic potential. In this study, we investigate the effect of a COX-2 selective inhibitor, NS398, on the expression and enzymatic activity of MMPs in human lung cancer cells. We found that NS398 inhibited MMP-2, not MMP-9, mRNA expression. NS398 also reduced the amount of MMP-2, not MMP-9, released into the medium. Additionally, this COX-2 inhibitor attenuated the degrading activity of MMP-2 as demonstrated by gelatin zymography. Investigation of cellular MMP-2 by Western blotting indicated that synthesis and processing of MMP-2 was significantly suppressed by NS398. We performed promoter activity assay to address whether NS398 might affect MMP-2 gene transcription. Our results indicated that NS398 directly inhibited MMP-2 promoter activity. However, the inhibitory effect of NS398 is not fully dependent on inhibition of COX-2 because a high concentration of NS398 was needed to suppress MMP-2 expression and addition of prostaglandin E2 only partially reversed the action of NS398. Moreover, a non-selective COX inhibitor indomethacin also suppressed the expression of MMP-2. Taken together, these results indicate that non-steroidal anti-inflammatory drugs suppress MMP-2 expression via repression of transcription and support the notion that COX inhibitors may be useful in inhibition and/or prevention of metastasis.
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PMID:Non-steroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 expression via repression of transcription in lung cancer cells. 1172 53

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

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

Matrix metalloproteinases (MMPs) are a pivotal family of zinc enzymes responsible for degradation of the extracellular matrix (ECM) components including basement membrane collagen, interstitial collagen, fibronectin, and various proteoglycans, during normal remodeling and repair processes. The potent proteolytic activities of MMPs is mainly regulated by the balance with specific tissue inhibitors of Matrix metalloproteinases (TIMP). Excessive or inappropriate expression of MMP may contribute to the pathogenesis of tissue destructive processes in a wide variety of diseases including lung diseases. Although the precise mechanisms are still unknown, the contribution of individual MMPs are worth investigating in seeking the pathogenesis of various lung diseases such as lung cancer, bronchial asthma, chronic obstructive pulmonary disease, acute lung injury, pulmonary hypertension and interstitial lung diseases. In particular, the close association of each lung disease with the destructive effects of gelatinase A and B (also called MMP-2 and MMP-9) on the basement membrane in early alveolar remodeling, and that of collagenase-1 (MMP-1) on the major interstitial structural protein of ECM have received considerable attention. The interaction of MMPs with chemical mediators and inflammatory cytokines has also been reported in some recent studies. Several promising therapeutic approaches to inhibit MMPs have just started in the field of oncology, while more specific MMP inhibitors may be required for further investigation in other fields of lung diseases. In this review, the main focus is on the recent clinical and experimental findings and the contributions of MMPs and/or TIMPs in the lung diseases.
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PMID:Matrix metalloproteinases in lung diseases. 1237 4

Cancer metastasis is tightly regulated by the interaction of tumor cells and host organ microenvironments. Matrix metalloproteinases (MMPs), produced by both tumor cells and host stromal cells, play a central role in tumor invasion and angiogenesis. We determined whether metastatic potential of lung cancer to multiple organs is dependent solely on the expression of MMPs by tumor cells, using two metastasis models of human lung cancer cell lines expressing various levels of MMPs and a MMP inhibitor (ONO-4817). In the lung metastasis model, tumor cells (PC14, PC14PE6, H226, A549) inoculated i.v. into nude or SCID mice metastasized only in the lung. In the multiple-organ metastasis model, tumor cells (RERF-LC-AI, SBC-3/DOX, H69/VP, which express low levels of MMPs) inoculated i.v. into natural killer cell-depleted SCID mice metastasized into the liver, kidneys, and systemic lymph nodes. Film in situ zymography analysis revealed that the nontumor parenchyma of the lung had no gelatinolytic activity, whereas gelatinolytic activity of the liver and kidney was high and low, respectively. In the lung metastasis model, gelatinolytic activity of lung nodules directly correlated with the in vitro expression of MMP-2 and MMP-9 by tumor cells. Inhibition of MMP activity by ONO-4817 suppressed lung metastasis by the cell lines that expressed MMPs, but not those that did not express MMP, via the inhibition of MMP activity of lung tumors. In the multiple-organ metastasis model, liver parenchyma, but not liver nodules, showed gelatinolytic activity. The MMP inhibition reduced metastasis to the liver, but not to the kidney or lymph nodes, via inhibition of MMP activity of liver parenchyma. These findings suggest that MMP expression varies among the host organ microenvironments and that stromal MMPs may promote metastasis of lung cancer. Therefore, antimetastatic effects based on MMP inhibition may be dependent on MMPs derived not only from tumor cells but also from organ-specific microenvironments.
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PMID:Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines. 1238 64

In this study we have evaluated the modifications of matrix metalloproteinases (MMPs) in malignant pleural fluids taken from patients suffering from lung cancer and treated with intrapleural talc instillation to induce pleurodesis. Furthermore, we have analysed the variations of some inflammatory mediators (C-reactive protein, alpha-1 antitrypsin) and of a protein (plasminogen) involved in MMP activation. In all patients the clinical improvement after talc pleurodesis was followed by a reduction in MMP-1, TIMP-1, C-reactive protein, alpha-1 antitrypsin and plasminogen activity. Furthermore, MMP-9 levels were variable; in fact, in some patients they were high at the beginning of treatment, in others they increased a few days after pleurodesis induction. These inhibitory effects of talc on MMP-1 and inflammatory mediators associated with the reduction of pleural effusion could constitute an effective means to evaluate the evolution of the treatment.
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PMID:Matrix metalloproteinases production in malignant pleural effusions after talc pleurodesis. 1297 66

Based on a previous report on the effect of a matrix metalloproteinase (MMP) inhibitory compound, MMI270, in regulating tumor-induced angiogenesis, as well as recent findings concerning functional correlations among tumor metastasis, angiogenesis and lymphangiogenesis, we investigated the anti-metastatic efficacy of MMI270 in a murine model of lymph node metastasis of lung cancer, and analyzed whether this inhibitor could also regulate lymphangiogenesis-related properties of murine lymphatic endothelial cells (LECs) and invasive properties of Lewis lung cancer (LLC) cells. The observation that MMI270 led to a significant decrease in the weight of tumor-metastasized lymph nodes of mice led us to test its anti-lymphangiogenic and anti-invasive effects in vitro. Murine LECs were characterized by an in vitro tube formation assay, by semi-quantitative RT-PCR assay to examine the expression of mRNAs for flt-4, Flk-1, Tie-1, Tie-2, CD54/ICAM1, vWF, MMPs and uPA, and by western blotting to confirm the protein expression of flt-4 and CD31/PECAM. This is the first report on the expression of MMP-2, MMP-9 and MT1-MMP in murine LECs, as well as on the inhibition of their enzymatic activity, and of the invasive ability and tube-forming property of LECs by an MMP inhibitor. Furthermore, MMI270 was shown to strongly inhibit the activity of MMP-2 and -9 produced by LLC cells and the invasion of these cells through Matrigel. In summary, the present results indicate that MMI270, apart from its anti-tumor angiogenic application, might be useful as an anti-metastatic drug, on the basis of its downregulatation of both the lymphangiogenesis-related properties of LECs and the invasive properties of LLC cells in vitro.
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PMID:Inhibition of lymphangiogenesis-related properties of murine lymphatic endothelial cells and lymph node metastasis of lung cancer by the matrix metalloproteinase inhibitor MMI270. 1472 Mar 23

This study was undertaken to examine the relationship between circulating matrix metalloproteinase (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in our patients with either advanced small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC) prior to treatment. Thirty-one male and female patients with either stage III or IV NSCLC and 17 with either stage III or IV SCLC were compared to 117 age matched non-smoking controls of both sexes. Prior to any treatment of the patient, a baseline serum sample was obtained from each of the patients for the determination of circulating MMP-9 and TIMP-1 by ELISA. The results indicate that both MMP-9 and TIMP-1 are elevated in the serum of lung cancer patients when compared to the controls. This observation was true for both SCLC and NSCLC. However, the mean values for both MMP-9 and TIMP-1 in the two tumors were not different from each other. The natural physiological relationship between MMP-9 and the inhibitor TIMP-1 was lost in both SCLC and NSCLC, indicative of abnormal alterations by the tumor. The data from this study suggests that advanced lung cancer does alter the normal circulatory pattern of MMP-9 and TIMP-1. This could aid in the processes of tumor invasion and/or metastasis.
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PMID:Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment. 1497 82

Growth factors secreted by either host or tumour cells play a major role in tumour cell progression. Besides stimulating cell division, growth factors may also stimulate cell migration and modulate matrix metalloprotease (MMP) production. MMPs are enzymes involved in a variety of physiological and pathological processes including tumour cell invasion and metastasis. We have previously shown that different growth factors regulate the motile behaviour of human lung cancer cell lines. In order to further advance our knowledge of the role the different growth factors play in lung cancer, we investigated their effect on two key enzymes belonging to the MMP family of enzymes, namely MMP-9 and MMP-2. Serum-free cultures of three human non-small cell lung cancer cell lines were exposed to five different growth factors: insulin-like growth factor I (IGF I) and II (IGF II), hepatocyte growth factor (HGF), epidermal growth factor (EGF) and stem cell factor (SCF). The expression of MMP-9 and MMP-2 in growth factor-treated and untreated cell lines was evaluated using gelatine zymography and quantified using computer-assisted image analyses. We found heterogeneous expression and activity of MMP-9 and MMP-2 in all three lung cancer cell lines. The most important finding in our study is that HGF and EGF are capable of stimulating the conversion of MMP-9 from a latent to an active form in human large cell lung cancer cell line U-1810 [corrected]. IGF I, IGF II, HGF and EGF stimulated an enhanced expression and activity of the latent form of MMP-2 and MMP-9. SCF did not enhance MMP activity in any of the cell lines tested. Our previous studies have shown that IGF I, IGF II, HGF, EGF and SCF induce migration of human non-small cell lung cancer cells in the presence of extracellular matrix (ECM) components. In the present study we show that growth factors can also enhance the expression of MMP's in these cells. Taken together these results indicate that certain growth factors may promote invasiveness through their ability to induce not only cell migration, but also by enhancing the expression and activity of matrix degrading MMP-2 and MMP-9.
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PMID:Growth factor-enhanced expression and activity of matrix metalloproteases in human non-small cell lung cancer cell lines. 1498 39

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