UMLS:C0684249 - FACTA Search

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The urokinase plasminogen activator(uPA) system plays important roles in tumor cell invasion and metastasis. In the present study, we evaluated the effects of ATF-PAI2CD, a hybrid protein of the amino-terminal fragment of urokinase and mutant plasminogen activator inhibitor-2, on 95D cells in vitro and in vivo. Furthermore, our results support a current hypothesis that fusion protein blocks tumor invasion and motility by inhibiting localized pericellular proteolysis. Treatment of 95D cells with ATF-PAI2CD resulted in a dose-dependent decrease in tumor-cell invasion through matrigel, and ATF-PAI2CD was much more effective than PAI-2CD. In addition, extracellular regular protein kinase (ERK1/2) expression was downregulated and the adhesion ability to fibronectin was increased in 95D cells treated with the fusion protein, which was confirmed by cell adhesion assay. A high-concentration of ATF-PAI2CD caused a significant reduction in tumor volume and weight in BALB/c (nu/nu) mice female inoculated with human 95D cells (5 x 10(6)); the antitumor effects were significant, which demonstrated a 67.9+/-4.2% reduction in tumor growth compared with control mice. The number of lymphatic metastasis was significantly reduced in mice treated with high- and middle- concentrations of ATF-PAI2CD, whereas a low-concentration of ATF-PAI2CD failed to exhibit any antimetastatic effects. In conclusion, the results suggested that the hybrid protein has therapeutic potential for lung carcinoma and other tumors to inhibit tumor invasion and metastasis.
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PMID:A hybrid protein of the amino-terminal fragment of urokinase and mutant plasminogen activator inhibitor-2 efficiently inhibits tumor cell invasion and metastasis. 1549 Feb 35

90K/Mac-2 Binding Protein (M2BP) plays a role in regulation of immune responses and cell adhesive ability in patients with cancer and infectious diseases. We previously reported that M2BP was highly expressed in lung cancer and that immune responses to M2BP were increased in many patients with lung cancer. To determine the involvement of M2BP in metastatic processes of cancer progression, we examined the ability of M2BP DNA-transduced lung carcinoma cell lines to adhere to extracellular matrices. Although expressions of cell-surface integrins were not modulated in the M2BP transfectants, they showed increased adhesiveness to fibronectin and collagen IV. We next analyzed the serum levels of M2BP in patients with lung cancer and normal donors and the relationships between M2BP expression and clinicopathological factors in the patients. The M2BP level was markedly elevated in the patients and was strongly correlated with nodal involvement and clinical staging. To determine whether expression of M2BP by cancer cells is modulated in the environment of tumor-bearing hosts, M2BP expression in M2BP-positive QG56 cells following exposure of the cells to pro-inflammatory cytokines was examined. The M2BP expression in QG56 cells was up-regulated by many of the cytokines that activate host protective immunity. The findings in this study suggest that M2BP plays a role in cancer metastasis by increased adhesiveness of cancer cells and that M2BP is increasingly produced even in a state of exposure to the host immune system. This molecule may be useful as a predictive factor of disease progression in lung cancer.
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PMID:Involvement of 90K/Mac-2 binding protein in cancer metastases by increased cellular adhesiveness in lung cancer. 1549 95

We previously showed that fibronectin stimulates the growth of non-small cell lung carcinoma (NSCLC) cells through integrin alpha5beta1-dependent signals. We also demonstrated that peroxisome proliferator-activated receptor (PPAR)gamma ligands inhibit lung carcinoma cell growth. Because alpha5beta1 activation elicits cellular signals linked to cell survival and regulation of cell cycle progression, we studied the effects of PPARgamma ligands on its expression. We found that PPARgamma ligands decreased mRNA and protein expression of the alpha5 subunit of the alpha5beta1 heterodimer in NSCLC; this was associated with reduced NSCLC adhesion to fibronectin. The suppressive effect of the PPARgamma ligands BRL 49653 and GW1929, but not PGJ(2), on alpha5 gene expression were reversed by GW9662, an antagonist of PPARgamma. GW1929 activated the extracellular regulated kinase (Erk), and an inhibitor of the Erk pathway (PD98095) prevented its effect on alpha5. PPARgamma ligands also reduced alpha5 gene promoter activity, and this was blocked by Erk antisense oligonucleotides. PPARgamma ligands GW1929 and BRL49653 inhibited AP-1 DNA binding, whereas 15d-PGJ(2) inhibited Sp1 DNA binding; both effects were blocked by Erk antisense oligonucleotides. GW1929 partially blocked fibronectin-induced NSCLC cell growth, but did not affect cell growth induced by epidermal growth factor. These results suggest that PPARgamma ligands inhibit alpha5 expression in NSCLC through Erk-related signals.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands inhibit alpha5 integrin gene transcription in non-small cell lung carcinoma cells. 2238 55

The cyclin-dependent kinase inhibitor p21(WAF-1/CIP1/MDA-6) (p21) plays a key role in cell cycle inhibition and apoptosis, and is negatively regulated during cell proliferation. Extracellular matrices can affect cellular proliferation, but their effects on p21 have not been entirely elucidated. Herein, we explore the effects of the matrix glycoprotein fibronectin on p21 expression in human lung carcinoma cells. Our studies show that fibronectin stimulates cell proliferation, and that this effect is associated with suppression of p21 and stimulation of cyclin D1 mRNA and protein levels in human lung non-small lung cell carcinoma cells (H1838). In contrast, the matrix protein collagen type 1 had no effect. The suppression of p21 by fibronectin was blocked by inhibitors of the extracellular signal-regulated kinase pathway (PD98095), and the Rho-kinase pathway (Y-27632). Fibronectin stimulated the phosphorylation of Erk and increased Rho protein expression. To determine the molecular mechanism(s) responsible for the inhibitory effects of fibronectin on p21 expression, transient transfection assays were performed with cells expressing a wild-type human p21 promoter construct. In these cells, fibronectin reduced p21 gene promoter activity. Finally, electrophoresis mobility shift experiments revealed that fibronectin decreased nuclear Sp1 binding activity in the promoter region of the p21 gene promoter, and a Sp1 competing oligonucleotide inhibited the fibronectin response. Taken together, our results suggest that fibronectin stimulates lung cancer carcinoma cell growth by reducing the cyclin-dependent kinase inhibitor p21 and by inducing cyclin D1 gene expression. The reduction of p21 by fibronectin appears to be mediated through Erk and Rho-kinase signaling and DNA-protein interactions at the Sp1 site in the p21 gene promoter. These observations unveil a novel mechanism for p21 gene regulation by fibronectin in lung carcinoma cell growth that represents a potential target for therapy.
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PMID:Fibronectin stimulates human lung carcinoma cell proliferation by suppressing p21 gene expression via signals involving Erk and Rho kinase. 1569 66

Tumor cell expression of COX-2 has been implicated in the progression of murine and human lung cancer. Inhibition of COX-2 by nonsteroidal antiinflammatory drugs reduces the risk of cancer development in humans and suppresses tumor growth in animal models. However, the underlying mechanisms for this beneficial effect are not fully understood. Here we explore the potential link between the anticancer effects of COX-2 inhibitors and the expression of the integrin alpha5beta1. Expression of this integrin in carcinoma cells is associated with invasiveness and malignant progression. This, together with our studies showing that fibronectin, the ligand of alpha5beta1, stimulates the growth of human lung carcinoma cells, and that this effect is mediated through alpha5beta1-dependent signals, has prompted us to examine the effects of COX-2 inhibitors on alpha5beta1 expression in human non small cell lung carcinoma (NSCLC) cells. We found that the selective COX-2 inhibitors NS398 and Nimesulide decreased mRNA expression and protein production of the integrin alpha5 subunit. This effect was associated with inhibition of NSCLC cell adhesion to fibronectin. The COX-2 inhibitors triggered the phosphorylation of extracellular signal-regulated kinase (Erk) in a time-dependent manner, and the inhibitor of Mek-1/Erk PD98095 prevented their inhibitory effects on integrin alpha5 expression. Transient transfection assays showed that the COX-2 inhibitors affected integrin alpha5 gene transcription by acting between -92 to -41 bp of the human integrin alpha5 gene promoter. Gel mobility shift assays showed that the COX-2 inhibitors increased Sp1 DNA binding, but decreased that of AP-1. These effects were accompanied by an increase in Sp1 protein and a decrease in c-Jun protein expression, as well as inhibition of SAPK/JNK phosphorylation. The Sp1 inhibitor, Mithramycin A, also blocked the inhibitory effect of the COX-2 inhibitors on alpha5 expression and promoter activity. Overall, these findings suggest that COX-2 inhibitors suppress alpha5beta1 integrin expression in NSCLC through effects on integrin alpha5 gene transcription mediated by Erk activation, increased Sp1, decreased AP-1 DNA binding and inactivation of SAPK/JNK signals. Our observations unveil a new mechanism of action against NSCLC for COX-2 inhibitors that relates to regulation of integrin alpha5 gene expression and, consequently, recognition of extracellular matrices (i.e., fibronectin) by tumor cells. (c) 2005 Wiley-Liss, Inc.
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PMID:COX-2 inhibitors suppress integrin alpha5 expression in human lung carcinoma cells through activation of Erk: involvement of Sp1 and AP-1 sites. 2625 13

Lung carcinoma often occurs in patients with chronic lung disease such as tobacco-related emphysema and asbestos-related pulmonary fibrosis. These diseases are characterized by dramatic alterations in the content and composition of the lung extracellular matrix, and we believe this "altered" matrix has the ability to promote lung carcinoma cell growth. One extracellular matrix molecule shown to be altered in these lung diseases is fibronectin (Fn). We previously reported increased growth and survival of non-small cell lung carcinoma (NSCLC) cells exposed to Fn. Thus Fn may serve as a mitogen/survival factor for NSCLC and therefore represents a novel target for anti-cancer strategies. To this end, we studied the effects of the PPARgamma ligands 15d-PGJ(2), rosiglitazone (BRL49653), and troglitazone on Fn expression in NSCLC cells and found that they were able to inhibit Fn gene transcription. Inhibition of Fn expression by BRL49653 and troglitazone, but not by 15d-PGJ(2), was prevented by the specific PPARgamma antagonist GW-9662 and by PPARgamma small interfering RNA. Working with Fn deletion and mutated promoter constructs, we found that the region between -170 and -50 bp downstream from the transcriptional start site of the promoter was involved in PPARgamma ligand inhibition. PPARgamma ligands also diminished the phosphorylation of CREB, diminished Sp1 nuclear protein expression, and prevented the binding of these transcription factors to CRE and Sp1 sites, respectively, within the Fn promoter. In summary, our results demonstrate that PPARgamma ligands inhibit Fn gene expression in NSCLC cells through PPARgamma-dependent and -independent pathways that affect both CREB and Sp1.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands suppress fibronectin gene expression in human lung carcinoma cells: involvement of both CRE and Sp1. 1590 79

We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique "compact" morphology compared to the "loose" morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1(+) vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1(+) vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.
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PMID:Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells. 1604 44

Treatment of second- and third-line patients with non-small-cell lung carcinoma (NSCLC) with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib significantly increased survival relative to placebo. Whereas patient tumors with EGFR mutations have shown responses to EGFR inhibitors, an exclusive role for mutations in patient survival benefit from EGFR inhibition is unclear. Here we show that wild-type EGFR-containing human NSCLC lines grown both in culture and as xenografts show a range of sensitivities to EGFR inhibition dependent on the degree to which they have undergone an epithelial to mesenchymal transition (EMT). NSCLC lines which express the epithelial cell junction protein E-cadherin showed greater sensitivity to EGFR inhibition in vitro and in xenografts. In contrast, NSCLC lines having undergone EMT, expressing vimentin and/or fibronectin, were insensitive to the growth inhibitory effects of EGFR kinase inhibition in vitro and in xenografts. The differential sensitivity of NSCLC cells with epithelial or mesenchymal phenotypes to EGFR inhibition did not correlate with cell cycle status in vitro or with xenograft growth rates in vivo, or with total EGFR protein levels. Cells sensitive to EGFR inhibition, with an epithelial cell phenotype, did exhibit increased phosphorylation of EGFR and ErbB3 and a marked increase in total ErbB3. The loss of E-cadherin and deregulation of beta-catenin associated with EMT have been shown to correlate with poor prognosis in multiple solid tumor types. These data suggest that EMT may be a general biological switch rendering non-small cell lung tumors sensitive or insensitive to EGFR inhibition.
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PMID:Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. 1623 Apr 9

The Akt/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (p70S6K) pathway is considered a central regulator of protein synthesis and of cell proliferation, differentiation, and survival. However, the role of the Akt/mTOR/p70S6K pathway in lung carcinoma remains unknown. We previously showed that fibronectin, a matrix glycoprotein highly expressed in tobacco-related lung disease, stimulates non-small cell lung carcinoma (NSCLC) cell growth and survival. Herein, we explore the role of the Akt/mTOR/p70S6K pathway in fibronectin-induced NSCLC cell growth. We found that fibronectin stimulated the phosphorylation of Akt, an upstream inducer of mTOR, and induced the phosphorylation of p70S6K1 and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), two downstream targets of mTOR in NSCLC cells (H1792 and H1838), whereas it inhibited the phosphatase and tensin homologue deleted on chromosome 10, a tumor suppressor protein that antagonizes the phosphatidylinositol 3-kinase/Akt signal. In addition, treatment with fibronectin inhibited the mRNA and protein expression of LKB1 as well as the phosphorylation of AMP-activated protein kinase (AMPKalpha), both known to down-regulate mTOR. Rapamycin, an inhibitor of mTOR, blocked the fibronectin-induced phosphorylation of p70S6K and 4E-BP1. Akt small interfering RNA (siRNA) and an antibody against the fibronectin-binding integrin alpha5beta1 also blocked the p70S6K phosphorylation in response to fibronectin. In contrast, an inhibitor of extracellular signal-regulated kinase 1/2 (PD98095) had no effect on fibronectin-induced phosphorylation of p70S6K. Moreover, the combination of rapamycin and siRNA for Akt blocked fibronectin-induced cell proliferation. Taken together, these observations suggest that fibronectin-induced stimulation of NSCLC cell proliferation requires activation of the Akt/mTOR/p70S6K pathway and is associated with inhibition of LKB1/AMPK signaling.
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PMID:Fibronectin stimulates non-small cell lung carcinoma cell growth through activation of Akt/mammalian target of rapamycin/S6 kinase and inactivation of LKB1/AMP-activated protein kinase signal pathways. 1639 45

The extracellular matrix glycoprotein, fibronectin, influences a variety of cellular functions including adhesion, migration, survival, differentiation, and growth. Fibronectin has also been shown to increase the migration and proliferation of human lung carcinoma cells. However, the role of fibronectin in controlling lung airway epithelial cell phenotype remains unknown. Here, we demonstrate that fibronectin stimulates the proliferation of human bronchial epithelial cells (BEAS-2B and 16-HBE). Of note, fibronectin induced the mRNA and protein expression of c-Myc and cyclin D1, while it decreased the expressions of cyclin-dependent kinase inhibitor p21 (WAF-1/CIP1/MDA-6) (p21) and the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome ten (PTEN). Fibronectin also stimulated the phosphorylation of the phosphatidylinositol 3 kinase (PI3-K) downstream signal Akt. The inhibitor of PI3-K, Wortmannin, and anti-alpha5beta1 integrin antibodies abrogated the effect of fibronectin on c-Myc, cyclin D1, p21, and PTEN expression. The stimulatory effect of fibronectin was mediated by nuclear factor kappaB (NF-kappaB) since fibronectin induced the expression of the p65 component of NF-kappaB and enhanced NF-kappaB DNA binding. Furthermore, we found that p65 small interfering RNA inhibited the effect of fibronectin on c-Myc, cyclin D1, p21, PTEN expression, and on fibronectin-induced cell proliferation. Finally, we found that fibronectin inhibits apoptosis by reducing DNA fragmentation and inhibiting the activities of caspases 3/7. Taken together, our findings demonstrate that fibronectin stimulates human bronchial epithelial cell growth and inhibits apoptosis through activation of NF-kappaB, which, in turn, increases the expression of c-Myc and cyclin D1 and decreases p21 and PTEN via alpha5beta1 integrin-dependent signals that include PI3-K/Akt. Therefore, alternations in the extracellular matrix composition of the lung, with increased fibronectin, might promote epithelial cell growth and thereby contribute to oncogenesis in certain settings.
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PMID:Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-kappa B. 1651 10

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