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

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

Significant improvements in the outcome of non-small cell lung carcinoma (NSCLC) have been reported in patients treated with the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. To discover biomarkers for the enrichment of patients who might benefit from treatment, a pharmacogenomic approach was used to identify gene signatures that may predict erlotinib activity using in vitro model systems. Erlotinib sensitivity in a panel of 42 NSCLC cell lines was determined by EGFR-mediated proliferative potential, EGFR mutations, and/or EGFR gene amplification, thus supporting an underlying biological mechanism of receptor activation. A strong multigene signature indicative of an epithelial to mesenchymal transition (EMT) was identified as a determinant of insensitivity to erlotinib through both supervised and unsupervised gene expression approaches. This observation was further supported by expression analysis of classic EMT marker proteins, including E-cadherin and vimentin. To investigate the clinical relevance of these findings, we examined expression of the epithelial marker E-cadherin by immunohistochemistry on primary tumor samples from subjects enrolled in a randomized NSCLC clinical trial in which erlotinib in combination with chemotherapy previously failed to show clinical activity. The majority (75%) of the 87 subjects tested showed strong E-cadherin staining and exhibited a significantly longer time to progression (hazard ratio, 0.37; log rank P=0.0028) and a nonsignificant trend toward longer survival with erlotinib plus chemotherapy treatment versus chemotherapy alone. These data support a potential role for EMT as a determinant of EGFR activity in NSCLC tumor cells and E-cadherin expression as a novel biomarker predicting clinical activity of the EGFR inhibitor erlotinib in NSCLC patients.
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PMID:Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. 1636 34

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.
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PMID:Immunohistochemical differential diagnosis between large cell neuroendocrine carcinoma and small cell carcinoma by tissue microarray analysis with a large antibody panel. 1670 68

The Wnt pathway is critical for normal development, and mutation of specific components is seen in carcinomas of diverse origins. The role of this pathway in lung tumorigenesis has not been clearly established. Recent studies from our laboratory indicate that combined expression of the combination of Wnt 7a and Frizzled 9 (Fzd 9) in Non-small Cell Lung Cancer (NSCLC) cell lines inhibits transformed growth. We have also shown that increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits transformed growth of NSCLC and promotes epithelial differentiation of these cells. The goal of this study was to determine whether the effects of Wnt 7a/Fzd 9 were mediated through PPARgamma. We found that Wnt 7a and Fzd 9 expression led to increased PPARgamma activity. This effect was not mediated by altered expression of the protein. Wnt 7a and Fzd 9 expression resulted in activation of ERK5, which was required for PPARgamma activation in NSCLC. SR 202, a known PPARgamma inhibitor, blocked the increase in PPARgamma activity and restored anchorage-independent growth in NSCLC expressing Wnt 7a and Fzd 9. SR 202 also reversed the increase in E-cadherin expression mediated by Wnt 7a and Fzd 9. These data suggest that ERK5-dependent activation of PPARgamma represents a major effector pathway mediating the anti-tumorigenic effects of Wnt 7a and Fzd 9 in NSCLC.
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PMID:Antitumorigenic effect of Wnt 7a and Fzd 9 in non-small cell lung cancer cells is mediated through ERK-5-dependent activation of peroxisome proliferator-activated receptor gamma. 1683 28

Hypermethylation occurs frequently in neoplastic cells and affects tumorigenesis. Malignant mesothelioma is an aggressive cancer developing in the thoracic cavity and patients have a rather bad prognosis. Our goal was to determine epigenetic alterations of a series of genes and to analyse the potential correlation of such changes with overall survival. We have analysed the methylation status of the promoter region of nine genes in serum DNA of mesothelioma patients by a nested methylation-specific PCR. Modest methylation frequencies were detected for APC1A (14.3%), RASSF1A (19.5%) and DAPK (20.0%) while hypermethylation of E-cadherin (71.4%) and FHIT (78.0%) occurred at a high incidence. Intermediate values were seen for p16(INK4a) (28.2%), APC1B (32.5%), p14(ARF) (44.2%) and RARbeta (55.8%). The methylation status of none of the single genes significantly influenced prognosis. In contrast, combining RARbeta with either DAPK or RASSF1A showed a significantly shorter overall survival of those patients who had both genes methylated compared to those with only one or no epigenetic alteration (P=0.025 and 0.040, respectively). Similarly, the combination of all three genes revealed a worse prognosis for patients with double or triple methylations compared to the group which had only one or no gene methylated (P=0.028). Our results support the idea that the prognostic value of a combination of epigenetic alterations is superior to the impact of an individual gene alone on overall survival.
Lung Cancer 2006 Oct
PMID:Promoter methylation of RASSF1A, RARbeta and DAPK predict poor prognosis of patients with malignant mesothelioma. 1689 90

Snail, Slug and Sip1 regulate cadherin and protease expression and mediate epithelial-mesenchymal transition in cancer. We analyzed the expression of cadherins and matrix metalloproteinases (MMP) and their transcriptional regulators in malignant mesothelioma (MM). One hundred and ten MM specimens (86 solid, 24 effusions) and 10 non-malignant effusions with reactive mesothelial cells (RMC) were analyzed for E-cadherin, N-cadherin and P-cadherin protein expression using immunhistochemistry. MM effusions were further analyzed for expression of Snail, Slug, Sip1, E-cadherin, MMP-2, MMP-9, MT1-MMP (MMP-14) and the MMP inhibitor TIMP-2, and for MMP-2 and MMP-9 activity using RT-PCR, Western blotting, immunhistochemistry and zymography. Results were analyzed for relationship with specimen type (biopsy versus effusion) and anatomic site (pleural versus peritoneal). E-cadherin, N-cadherin and P-cadherin expression was found in 69/110 (63%), 87/110 (79%) and 84/110 (76%) MM cases, respectively. Pleural and peritoneal MM showed comparable expression, but all three cadherins were upregulated in effusions compared to solid tumors (p<0.001). RMC were uniformly negative for E-cadherin and N-cadherin, and showed P-cadherin expression in 7/10 specimens. Immunohistochemistry localized MMP-2, MMP-9 and TIMP-2 to MM cells in 11/15, 14/15 and 8/15 effusions, respectively. RT-PCR showed direct association between MMP-2 mRNA expression level and the levels of MT1-MMP (p=0.027) and TIMP-2 (p=0.011). Snail protein expression showed positive association with MT1-MMP (p=0.016) and TIMP-2 (p=0.02) mRNA expression, but its expression was unrelated to MMP-2 and MMP-9 expression or activity. Snail, Slug and Sip1 levels did not show inverse association with E-cadherin levels. Our data show that E-cadherin and N-cadherin are selectively expressed in malignant mesothelial cells, and that P-cadherin and N-cadherin are expressed with similar frequency in MM. In agreement with our earlier data for ovarian carcinoma, cadherin expression is upregulated in effusions compared to solid lesions. The increased E-cadherin expression in effusions may be related to lack of negative regulation at the epigenetic level. The relationship between Snail and MMP in MM is uncertain at present.
Lung Cancer 2006 Dec
PMID:Expression of Snail, Slug and Sip1 in malignant mesothelioma effusions is associated with matrix metalloproteinase, but not with cadherin expression. 1699 43

The modest response of patients with head and neck squamous cell carcinoma (HNSCC) and non-small cell lung carcinoma (NSCLC) to epithelial growth factor receptor tyrosine kinase inhibitors such as gefitinib and erlotinib indicates the need for the development of biomarkers to predict response. We determined gefitinib sensitivity in a panel of HNSCC cell lines by a 5-day 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and confirmed these responses with analysis of downstream signaling by immunoblotting and cell cycle arrest. Basal gene expression profiles were then determined by microarray analysis and correlated with gefitinib response. These data were combined with previously reported NSCLC microarray results to generate a broader predictive index. Common markers of resistance between the two tumor types included genes associated with the epithelial to mesenchymal transition. We confirmed that increased protein expression of vimentin combined with the loss of E-cadherin, claudin 4, and claudin 7 by immunoblotting was associated with gefitinib resistance in both HNSCC and NSCLC cell lines. In addition, the loss of the Ca(2+)-independent cell-cell adhesion molecules EpCAM and TROP2 in resistant lines was confirmed by immunofluorescence. Tumor xenografts derived from the gefitinib-sensitive UM-SCC-2 were growth-delayed by gefitinib, whereas the gefitinib-resistant 1483 xenografts were unaffected. These data support a role for epithelial to mesenchymal transition in establishing gefitinib resistance for both HNSCC and NSCLC, and indicate that clinical trials should address whether these biomarkers will be useful for patient selection.
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PMID:Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. 1754 Oct 31

We report 4 cases of pseudomesotheliomatous carcinoma of the lung, which has clinical and microscopic features similar to malignant mesothelioma, but with ultrastructural, immunohistochemical, and molecular characteristics suggestive of a histogenesis from type II pneumocytes. Neoplasm grows as a diffuse or solid pattern of large polygonal cells with sharply defined borders. Hale's colloidal iron is positive in the cytoplasm of small groups of cells and, focally, in some intercellular spaces. Ultrastructure showed short microvilli in the surface. Immunohistochemically, tumor cells were positive for thyroid transcription factor-1, podoplanin, mesothelin, pan-cytokeratin, CK-7, CK-19, Ber-EP4, epithelial membrane antigen, apoprotein surfactant A, epidermal growth factor receptor, Leu-M1, carcinoembryonic antigen, E-cadherin, and CD-44 and negative for mesothelioma markers thrombomodulin and calretinin. In some areas, there were small cysts which contained a concentric fibrilar basophilic material apoprotein surfactant A positive. Chromosomal imbalances with comparative genomic hybridization technique were identified with a median of 15 abnormalities per case (range, 1-26): 51 gains, 6 losses, and 1 high-level amplification. The most frequent aberrations among the cases were gains on chromosomes regions 1q, 3q, 5p, 8q, 16p, and 18q and losses in 17p11-13 and 17q 22-q25. High-level amplifications were detected on 7p13-p21. In all cases, there was a characteristic association between the gains on 16p and those on 18q. The 4 cases resulted in death in less than 14 months, in spite of complete surgery and chemotherapy in 2 cases. Our aim is to complement the current understanding of this pseudomesotheliomatous "pneumocytic" carcinoma and alert pathologists to this rare entity to avoid misdiagnosis.
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PMID:Pseudomesotheliomatous carcinoma of the lung with a distinct morphology, immunohistochemistry, and comparative genomic hybridization profile. 1763 Jan 7

Hypermethylation of CpG islands is well known as a major inactivation mechanism of tumor suppressor genes. E-cadherin (E-cad) as a tumor invasion suppressor has been reported in several invasive and metastatic carcinomas. However, its significance in carcinogenesis of primary non-small cell lung cancer (NSCLC) is not well documented. This study was designed to assess the significance with 95 pairs of carefully collected NSCLC tumors and corresponding nonmalignant tissue samples. We carried out PCR-SSCP (single-strand conformation polymorphism) and PCR-RFLP (restriction fragment length polymorphism) screening for DNA variants, bisulfite conversion-specific MSP for methylation analysis, reverse transcription (RT)-PCR for mRNA and immunohistochemistry (IHC) for protein expression assays. To investigate effect of promoter-hypermethylation on E-cad expression, we also did demethylation experiment in six cell lines. First, we found that the -160A carriers (a single nucleotide polymorphism (SNP) in the promoter region of E-cad) had an increased risk for lung cancer development when compared to DNA from healthy volunteers (OR (odds ratio)=2.81; 95% CI (confidence interval), 1.36-5.86). Methylation of E-cad occurred with a significantly higher frequency in tumors than corresponding normal peritumoral tissues (P<10(-5)). Reduced expression of E-cad was detected as a distinct molecular feature of tumors in comparison to corresponding counterparts. Moreover, the methylation alteration was detected more frequently in low-differentiated tumors than in well-differentiated ones. Defective expression of E-cad in methylated cell lines was markedly recovered after treated with 5-Aza-dC (5-aza-2'-deoxycytidine). Thus, promoter-hypermethylation of E-cad is significantly associated with its defective expression and tumor differentiation, and the demethylating observation proposes a therapeutic strategy to reverse the tumor's malignancy by restoring normal expression of E-cad.
Lung Cancer 2008 Nov
PMID:Promoter-hypermethylation associated defective expression of E-cadherin in primary non-small cell lung cancer. 1846 19

The small G-protein Rap1 is a critical regulator of cell-cell contacts and is activated by the remodeling of adherens junctions. Here we identify the Rap1 guanine nucleotide exchange factor PDZ-GEF2 as an upstream activator of Rap1 required for the maturation of adherens junctions in the lung carcinoma cells A549. Knockdown of PDZ-GEF2 results in the persistence of adhesion zippers at cell-cell contacts. Activation of Rap1A rescues junction maturation in absence of PDZ-GEF2, demonstrating that Rap1A is downstream of PDZ-GEF2 in this process. Moreover, depletion of Rap1A, but not Rap1B, impairs adherens junction maturation. siRNA for PDZ-GEF2 also lowers the levels of E-cadherin, an effect that can be mimicked by Rap1B, but not Rap1A siRNA. Since junctions in Rap1B depleted cells have a mature appearance, these data suggest that PDZ-GEF2 activates Rap1A and Rap1B to perform different functions. Our results present the first direct evidence that PDZ-GEF2 plays a critical role in the maturation of adherens junctions.
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PMID:The RapGEF PDZ-GEF2 is required for maturation of cell-cell junctions. 1858 5


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