Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the anti-invasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time- and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.
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PMID:Upregulation of tissue inhibitor of matrix metalloproteinases-1 confers the anti-invasive action of cisplatin on human cancer cells. 1736 56

Flavanones richly exist in citrus and have been well characterized to have various bioactive properties. However, the anti-metastasis properties of flavanones remain unclear. The anti-metastatic effects of six flavanones including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, naringin, and naringenin were investigated in lung cancer cells. Despite little influence on cell viability, flavanone and 2'-OH flavanone markedly inhibited the invasion, motility, and cell-matrix adhesion of A549 cells. This was associated with a reduced expression of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA) in treated cells. Treatment with flavanone and 2'-OH flavanone also potently attenuated the phosphorylations of extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38(MAPK), as well as the activations of NF-kappaB and AP-1. The reduced expressions of MMP-2 and u-PA, as well as inhibition of cell invasion were obtained in the cultures treated with U0126 (ERK 1/2 inhibitor) and SB203580 (p38(MAPK) inhibitor). Thus, the inhibitory effects of flavanone and 2'-OH flavanone on the expression of MMP-2 and u-PA may be at least partly through inactivation of ERK 1/2 and p38(MAPK) signaling pathways. Finally, oral administration of flavanone and 2'-OH flavanone were evidenced by its inhibition on the metastasis of A549 cells and Lewis lung carcinoma (LLC) cells in vivo. In conclusion, flavanone and 2'-OH flavanone perturb the invasion and metastasis of lung cancer cells, thereby constituting an adjuvant treatment for metastasis control.
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PMID:Flavanone and 2'-OH flavanone inhibit metastasis of lung cancer cells via down-regulation of proteinases activities and MAPK pathway. 1737 16

The brain is frequently affected by the spread of lung cancer, and haematogenous metastasis is a common route to brain metastasis. We therefore developed an isogenic brain metastasis model of lung cancer to use the Lewis lung carcinoma cell line and analysed dynamics of neoplastic cells after extravasation. Histological analysis revealed two characteristic patterns: metastatic foci exhibiting an angiocentric pattern were designated 'perivascular proliferations'; neoplastic cells infiltrating the brain parenchyma were designated 'invasive proliferations'. Electron microscopic observation of perivascular proliferations showed that neoplastic cells were confined to the perivascular space. In invasive proliferations, however, fragments of collagen fibre were observed in the gaps between neoplastic cells, indicating that the neoplastic cells had disintegrated the pia-glial membrane. We analysed the expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 by using both immunohistochemical analysis and real-time polymerase chain reaction analysis. MMP-2 expression was significantly higher in invasive proliferations. MMP-9 expression was significantly higher in day 7, but there was no significant difference in day 11. The pia-glial membrane and perivascular space are the barriers that neoplastic cells must overcome to infiltrate the brain. In conclusion, our findings suggest that brain metastasis requires two distinct processes.
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PMID:A double three-step theory of brain metastasis in mice: the role of the pia mater and matrix metalloproteinases. 1749 10

The syndecans comprise a family of cell surface heparan sulfate proteoglycans exhibiting complex biological functions involving the interaction of heparan sulfate side chains with a variety of soluble and insoluble heparin-binding extracellular ligands. Here we demonstrate an inverse correlation between the expression level of syndecan-2 and the metastatic potential of three clones derived from Lewis lung carcinoma 3LL. This correlation was proved to be a causal relationship, because transfection of syndecan-2 into the higher metastatic clone resulted in the suppression of both spontaneous and experimental metastases to the lung. Although the expression levels of matrix metalloproteinase-2 (MMP-2) and its cell surface activators, such as membrane-type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinase-2, were similar regardless of the metastatic potentials of the clones, elevated activation of MMP-2 was observed in the higher metastatic clone. Removal of heparan sulfate from the cell surface of low metastatic cells by treatment with heparitinase-I promoted MMP-2 activation, and transfection of syndecan-2 into highly metastatic cells suppressed MMP-2 activation. Furthermore, transfection of mutated syndecan-2 lacking glycosaminoglycan attachment sites into highly metastatic cells did not have any suppressive effect on MMP-2 activation, suggesting that this suppression was mediated by the heparan sulfate side chains of syndecan-2. Actually, MMP-2 was found to exhibit a strong binding ability to heparin, the dissociation constant value being 62 nM. These results indicate a novel function of syndecan-2, which acts as a suppressor for MMP-2 activation, causing suppression of metastasis in at least the metastatic system used in the present study.
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PMID:A novel function of syndecan-2, suppression of matrix metalloproteinase-2 activation, which causes suppression of metastasis. 1762 63

It has been reported that an endogenous matrix metalloproteinase (MMP) inhibitor, reversion-inducing cysteine-rich protein with Kazal motifs (RECK), is able to inhibit tumour angiogenesis, invasion, and metastasis through inhibition of MMP-2, MMP-9, and membrane type-1 (MT1)-MMP (MMP-14) secretion and activity. In this study, using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR), we have analysed RECK expression levels in resected non-small-cell lung cancer (NSCLC) tissue and compared these data with the clinicopathological features of these patients to investigate the role of RECK in NSCLC. We have also analysed the expression of MMP-2, MMP-9, and MMP-14 and compared the data with those for RECK expression. Tissue samples of primary lung cancers were obtained from a total of 83 patients [46 with adenocarcinomas (ADC) and 37 with squamous cell carcinomas (SCC)] who underwent curative resection. The samples were taken from 83 tumours and 20 matched normal lung tissue samples as controls. Expressions of RECK in ADC and SCC were significantly lower than in the control. In ADC tissue, the expression of RECK was higher in stage IA than in stage IB-IIIA. There was no such a correlation in SCC. In ADC, univariate analysis for relapse-free survival using Cox regression analysis identified low RECK expression (p=0.036), low MMP-14 expression (p=0.038), and tumour T2 (p=0.034) as significant negative prognostic predictors. However, in SCC, none of the clinicopathological factors assessed, including RECK expression, had prognostic value. In conclusion, our study suggests that suppression of RECK expression is involved in the progression of ADC of the lung and that RECK expression in resected ADC of the lung is a favorable predictor of patients' prognosis.
Lung Cancer 2007 Dec
PMID:Low expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) indicates a shorter survival after resection in patients with adenocarcinoma of the lung. 1771 26

The focus of the present study was whether and how infiltrating macrophages play a role in angiogenesis and the growth of cancer cells in response to the inflammatory cytokine interleukin (IL)-1beta. Lewis lung carcinoma cells overexpressing IL-1beta grew faster and induced greater neovascularization than a low IL-1beta-expressing counterpart in vivo. When macrophages were depleted using clodronate liposomes, both neovascularization and tumor growth were reduced in the IL-1beta-expressing tumors. Co-cultivation of IL-1beta-expressing cancer cells with macrophages synergistically augmented neovascularization and the migration of vascular endothelial cells. In these co-cultures, production of the angiogenic factors vascular endothelial growth factor-A and IL-8, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 were increased markedly. The production of these factors, induced by IL-1beta-stimulated lung cancer cells, was blocked by a nuclear factor (NF)-kappaB inhibitor, and also by the knockdown of p65 (NF-kappaB) and c-Jun using small interference RNA, suggesting involvement of the transcription factors NF-kappaB and AP-1. These results demonstrated that macrophages recruited into tumors by monocyte chemoattractant protein-1 and other chemokines could play a critical role in promoting tumor growth and angiogenesis, through interactions with cancer cells mediated by inflammatory stimuli.
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PMID:Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. 1792 76

Natural cytotoxicity receptors and NKG2D correspond to major activating receptors involved in triggering of tumor cell lysis by human NK cells. In this report, we investigated the expression of NKG2D ligands (NKG2DLs), MHC class I-related chain (MIC) A, MICB and UL16-binding proteins 1, 2 and 3, on a panel of human non-small-cell lung carcinoma cell lines, and we analyzed their role in tumor cell susceptibility to NK cell lysis. Although adenocarcinoma (ADC) cells expressed heterogeneous levels of NKG2DLs, they were often resistant to NK cell-mediated killing. Resistance of a selected cell line, ADC-Coco, to allogeneic polyclonal NK cells and autologous NK cell clones correlated with shedding of NKG2DLs resulting from a matrix metalloproteinase (MMP) production. Treatment of ADC-Coco cells with a MMP inhibitor (MMPI) combined with IL-15 stimulation of autologous NK cell clones lead to a potentiation of NK cell-mediated cytotoxicity. This lysis is mainly NKG2D mediated, since it is abrogated by anti-NKG2D-neutralizing mAb. These results suggest that MMPIs, in combination with IL-15, may be useful for overcoming tumor cell escape from the innate immune response.
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PMID:Potentiation of NK cell-mediated cytotoxicity in human lung adenocarcinoma: role of NKG2D-dependent pathway. 1844 40

Clinically relevant animal models of human cancer are necessary for the evaluation of putative therapeutics. We hypothesized that circulating human lung cancer-associated proteins would correlate with physiologic measurements from an orthotopic H460 human non-small cell lung carcinoma model that we developed in immunodeficient rats. Physiologic measurements and serum samples were collected over time. Serum interleukin-8 (IL-8), p53, vascular endothelial growth factor, and matrix metalloproteinase-9 were quantitated for correlation with physiologic measurements. Matrix metalloproteinase-9 and p53 were not significantly detectable. Circulating vascular endothelial growth factor was detected at high levels in some tumor-bearing animals. Human IL-8 was detectable in all tumor-bearing animals and correlated positively with markers of respiratory acidosis (pH, P = 0.012; TCO(2), P = 0.024; pCO(2), P = 0.007; and HCO(3)(-), P = 0.029) and with surface body temperature (P = 0.001) beginning on day 16 after implantation. IL-8 levels negatively correlated with survival (P < 0.001), indicating an association with tumor burden. Circulating human IL-8 might be a useful, clinically relevant circulating tumor protein marker due to its positive correlation with multiple physiologic variables associated with lung cancer progression.
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PMID:Circulating human interleukin-8 as an indicator of cancer progression in a nude rat orthotopic human non-small cell lung carcinoma model. 1870 12

Epilysin (MMP-28) is the newest member of the matrix metalloproteinase (MMP) family of extracellular proteases. Together the MMPs can degrade almost all components of the extracellular matrix (ECM). MMPs also regulate cell behaviour by releasing growth factors and biologically active peptides from the ECM by modulating cell surface receptors and adhesion molecules and by regulating the activity of mediators of the inflammatory pathways. Epilysin differs from most other MMPs as it is expressed in a number of normal tissues, suggestive of functions in tissue homeostasis. The epilysin homologue in Xenopus laevis (XMMP-28) is expressed in neural tissues, where it cleaves the neural cell adhesion molecule. Enhanced expression of epilysin has been observed in basal keratinocytes during wound healing and in different forms of cancer. There are, however, also reports on the downregulation of epilysin in malignant cells. The roles of epilysin in cancer seem to vary based on tumor type and stage of the disease. Importantly, epilysin can induce stable epithelial to mesenchymal transition (EMT) when overexpressed in epithelial lung carcinoma cells. Transforming growth factor beta (TGF-beta) is a crucial mediator of this process, which was characterized by the loss of E-cadherin and increased cell migration and invasion. Current results suggest a plausible interaction between epilysin and TGF-beta also under physiological circumstances, where epilysin activity may not induce EMT but, instead, trigger less permanent changes in TGF-beta signalling and cell motility.
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PMID:Epilysin (MMP-28)--structure, expression and potential functions. 1880 61

Small-cell lung cancer (SCLC) accounts for almost 15% of lung carcinomas. Chemotherapy is the cornerstone of treatment of patients with SCLC. In limited disease, median survival is about 12-20 months, with no more than 6%-12% of patients surviving beyond 5 years. In extensive disease, median survival is 7-12 months, with < 5% of patients living beyond 2 years and a 5-year survival rate of just 2%. Several therapeutic approaches have been used in an attempt to improve the outcome of SCLC. Among these, a better understanding of tumor biology and the subsequent development of novel therapeutic strategies have been identified as a possible approach for increasing the survival rate of patients with SCLC. Several targeted agents have been introduced into clinical trials in SCLC, and a few phase III studies, including matrix metalloproteinase inhibitors, thalidomide, and vaccines, have already produced definitive results. Currently, negative results are more commonly reported than positive ones. However, this first generation of clinical trials represents only the beginning of clinical research in this field. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. Nevertheless, clinical research in this field is still in progress considering that several new targeted agents, such as antiangiogenic agents and mammalian target of rapamycin inhibitors, offer a promise of improved outcomes. This review will focus on the reported results and the future development of the main novel biologic agents for the treatment of patients with SCLC.
Clin Lung Cancer 2008 Sep
PMID:New targeted therapies and small-cell lung cancer. 1882 49


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