Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Malignant pleural effusion (PE) is one of the poor prognostic factors in non-small cell lung cancer (NSCLC), and the detailed mechanism of the malignant PE formation is not fully elucidated. Recently, CXCR4, a receptor for chemokine stromal-derived factor-1alpha (SDF-1alpha) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1alpha/CXCR4 axis may be involved in the dissemination of malignant cells into pleural space, and investigated its expression, function, and signaling pathway using NSCLC cell lines and clinical samples from 43 patients with NSCLC with malignant PE. We found functional expression of CXCR4 on NSCLC cell lines, and also found that SDF-1alpha could induce migration via phosphatidylinositol 3 (PI-3) kinase- and p44/42 mitogen-activated protein kinase-dependent manner. The SDF-1alpha levels in malignant PE were significantly higher than those in transudate PE and showed a significant positive correlation with PE volumes. The sensitivity and specificity for prediction of recurrence of malignant PE was 61.5% and 83.3%, respectively (cutoff SDF-1alpha = 2,500 ng/ml), and better than those using pH of PE. Cancer cells in malignant PE expressed CXCR4, and mesothelial cells of the pleura stained positive for SDF-1alpha. The SDF-1alpha/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.
Am J Respir Cell Mol Biol 2004 May
PMID:Stromal-derived factor-1alpha/CXCL12-CXCR 4 axis is involved in the dissemination of NSCLC cells into pleural space. 1869 64

Multiplex methylation-sensitive PCR was employed in studying the methylation of CpG islands in the RB1, p16/CDKN2A, p15/CDKN2B, p14/ARF, CDH1, HIC1, and N33 5' regions in non-small cell lung cancer (51 tumors). Methylation was observed for the two suppressor genes involved in controlling the cell cycle through the Cdk-Rb-E2F signaling pathway, RB1 (10/51, 19%) and p16 (20/51, 39%). The highest methylation frequencies were established for CDH1 (72%) and HIC1 (82%). The CpG islands of p14 and p15 proved to be nonmethylated. At least one gene was methylated in 90% (46/51) tumors and no gene, in 10% (5/51) tumors. In addition, the genes were tested for methylation in peripheral blood lymphocytes of healthy subjects. Methylation frequency significantly differed between tumors and normal cells in the case of RB1, p16, CDH1, HIC1, and N33. Gene methylation frequency was tested for association with histological type of the tumor and stage of tumor progression. Methylation index of a panel of tumor suppressor genes was established for groups of tumors varying in clinical and morphological parameters.
Mol Biol (Mosk)
PMID:[Profile of methylation of certain tumor growth suppressing genes in non-small cell lung cancer]. 1471 93

The classification of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) can pose diagnostic problems due to inter-observer variability and other limitations of histopathology. There is an interest in developing classificatory models of lung neoplasms based on the analysis of multivariate molecular data with statistical methods and/or neural networks. DNA methylation levels at 20 loci were measured in 41 SCLC and 46 NSCLC cell lines with the quantitative real-time PCR method MethyLight. The data were analyzed with artificial neural networks (ANN) and linear discriminant analysis (LDA) to classify the cell lines into SCLC or into NSCLC. Models used either data from all 20 loci, or from five significant DNA methylation loci that were selected by a step-wise back-propagation procedure (PTGS2, CALCA, MTHFR, ESR1, and CDKN2A). The data were sorted randomly by cell line into 10 different data sets, each with training and testing subsets composed of 71 and 16 of the cases, respectively. Ten ANN models were trained using the 10 data sets: five using 20 variables, and five using the five variables selected by step-wise back-propagation. The ANN models with 20 input variables correctly classified 100% of the cell lines, while the models with only five variables correctly classified 87 to 100% of cases. For comparison, 10 different LDA models were trained and tested using the same data sets with either the original data or with logarithmically transformed data. Again, half of the models used all 20 variables while the others used only the five significant variables. LDA models provided correct classifications in 62.5% to 87.5% of cases. The classifications provided by all of the different models were compared with kappa statistics, yielding kappa values ranging from 0.25 to 1.0. We conclude that ANN models based on DNA methylation profiles can objectively classify SCLC and NSCLC cells lines with substantial to perfect concordance, while LDA models based on DNA methylation profiles provide poor to substantial concordance. Our work supports the promise of ANN analysis of DNA methylation data as a powerful approach for the development of automated methods for lung cancer classification.
J Mol Diagn 2004 Feb
PMID:Classification of individual lung cancer cell lines based on DNA methylation markers: use of linear discriminant analysis and artificial neural networks. 1473 24

The leading European and American professional societies recommend that bone scans (BS) should be performed in the staging of lung cancer only in those patients with bone pain. This prospective study investigated the sensitivity of conventional skeletal scintigraphy in detecting osseous metastases in patients with lung cancer and addressed the potential consequences of failure to use this method in the work-up of asymptomatic patients. Subsequent to initial diagnosis of non-small cell lung cancer, 100 patients were examined and questioned regarding skeletal complaints. Two specialists in internal medicine decided whether they would recommend a bone scan on the basis of the clinical evaluation. Skeletal scintigraphy was then performed blinded to the findings of history and physical examination. The combined results of magnetic resonance imaging (MRI) of the vertebral column, positron emission tomography (PET) of skeletal bone and the subsequent clinical course served as the gold standard for the identification of osseous metastases. Bone scintigraphy showed an 87% sensitivity in the detection of bone metastases. Failure to perform skeletal scintigraphy in asymptomatic patients reduced the sensitivity of the method, depending on the interpretation of the symptoms, to 19-39%. Without the findings of skeletal scintigraphy and the gold standard methods, 14-22% of patients would have undergone unnecessary surgery or neoadjuvant therapy. On this basis it is concluded that bone scans should not be omitted in asymptomatic patients.
Eur J Nucl Med Mol Imaging 2004 Jul
PMID:Omission of bone scanning according to staging guidelines leads to futile therapy in non-small cell lung cancer. 1499 Dec 41

Gefitinib (Iressa, ZD1839), a quinazoline tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR), is approved for patients with advanced non-small cell lung cancer (NSCLC) in several countries including Japan. However, the mechanism of drug sensitivity to gefitinib is not fully understood. In this study, we examined the molecular basis of sensitivity to gefitinib using nine human lung cancer cell lines derived from NSCLC. PC9 was the most sensitive to gefitinib of the nine NSCLC cell lines when assayed either by colony formation or MTS assays. The various cell lines expressed different levels of EGFR, HER2, HER3, and HER4, but there was no correlation between levels of EGFR and/or HER2 expression and drug sensitivity. Phosphorylation of EGFR, protein kinase B/AKT (Akt), and extracellular signal-regulated kinase (ERK) 1/2 was inhibited by much lower concentration of gefitinib in PC9 cells than in the other eight cell lines under exponential growing conditions. About 80% of cell surface EGFR in PC-9 was internalized within 10 min, whereas only about 30-50% of the cell surface EGFR was internalized in more drug-resistant cell lines in 15-60 min. The present study is the first to demonstrate that sensitivity to growth inhibition by gefitinib in NSCLC cell lines under basal growth condition is associated with dependence on Akt and ERK1/2 activation in response to EGFR signaling for survival and proliferation and also that drug sensitivity may be related to the extent of EGF-induced down-regulation of cell surface EGFR.
Mol Cancer Ther 2004 Apr
PMID:Sensitivity to gefitinib (Iressa, ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor (EGF) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation. 1507 90

LRP1b and the closely related LRP1 are large members of the low-density lipoprotein receptor family. At the protein level LRP1b is 55% identical to LRP1, a multifunctional and developmentally essential receptor with roles in cargo transport and cellular signaling. Somatic LRP1b mutations frequently occur in non-small cell lung cancer and urothelial cancers, suggesting a role in the modulation of cellular growth. In contrast to LRP1, LRP1b-deficient mice develop normally, most likely due to its restricted expression pattern and functional compensation by LRP1 or other receptors. LRP1b is expressed predominantly in the brain, and a differentially spliced form is present in the adrenal gland and in the testis. Despite the presence of a potential furin cleavage site and in contrast to LRP1, immunoblotting for LRP1b reveals the presence of a single 600-kDa polypeptide species. Using a yeast two-hybrid approach, we have identified two intracellular proteins, the postsynaptic density protein 95 and the aryl hydrocarbon receptor-interacting protein, that bind to the intracellular domain of LRP1b. In addition, we have found several potential ligands that bind to the extracellular domain. Analysis of LRP1b knockout mice may provide further insights into the role of LRP1b as a tumor suppressor and into the mechanisms of cancer development.
Mol Cell Biol 2004 May
PMID:Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1. 1508 73

This review summarizes the current literature and tries to define the status of nuclear medicine in the clinical workup of lung cancer patients. Nuclear medicine procedures and positron emission tomography (PET) with the EMEA-approved radiopharmaceutical fluorodeo-xyglucose (FDG) are indicated for the characterization of lung lesions; the nodal staging of non-small cell lung cancer (NSCLC); the detection of distant metastases; and for the diagnosis of recurrent disease. Recent studies have shown the clinical efficacy of nuclear medicine and especially of FDG-PET in the workup of lung cancer patients and its significant impact on patients' management. Conventional nuclear medicine procedures are established for the pre-therapeutic assessment of pulmonary perfusion and function (lung perfusion and ventilation scintigraphy) and for the detection of bone metastases (skeletal scintigraphy). In studies in thousands of patients, FDG-PET has been proved to be the most accurate non-invasive diagnostic test for the characterization of lung nodules and masses. It can be recommended at least for patients with increased risk at surgery. FDG-PET should be applied in candidates for surgery of lung cancer, as mediastinoscopy may be omitted if PET shows no metastases in the mediastinum, and because FDG-PET avoids futile surgery by a more accurate selection of patients, especially by the detection of unexpected distant metastases. In candidates for thoracic radiotherapy, FDG-PET can help to exclude extrathoracic disease which needs systemic treatment and to better define the target volume for radiation therapy. The time has come for FDG-PET to find its place in new guidelines for the workup of lung cancer patients.
Q J Nucl Med Mol Imaging 2004 Jun
PMID:Position of nuclear medicine modalities in the diagnostic workup of cancer patients: lung cancer. 1524 8

CD24 is a molecule that recently has raised considerable attention in tumour biology. It is involved in cell adhesion and metastatic tumour spread. It has also been described as a new diagnostic marker of tumours, of neuroendocrine differentiation and, possibly most intriguing of all, of patient prognosis. High rates of CD24 expression detected by immunohistochemistry have been found in epithelial ovarian cancer (83%), breast cancer (85%), non-small cell lung cancer (45%), prostate cancer (48%) and pancreatic cancer (72%). With the exception of pancreatic cancer, high rates of CD24 are significantly associated with a more aggressive course of the disease, a finding that remains significant in a multivariate analysis. The aim of this review is to summarize relevant work covering these aspects of CD24.
J Mol Histol 2004 Mar
PMID:Tumour biological aspects of CD24, a mucin-like adhesion molecule. 1533 45

Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.
Hum Mol Genet 2004 Dec 15
PMID:Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839). 1549 27

The expression of selected gene products involved in cell differentiation and cell growth and genetic polymorphism of detoxifying genes was examined in 105 surgically resected nonsmall cell lung cancer (NSCLC) patients, and the relationship of these factors was correlated with cigarette smoking and patient survival. Genotyping of peripheral blood lymphocytes from 87 patients was performed for CYP2E1, GSTM1, GSTT1, mEH, and MPO detoxifying genes using polymerase chain reaction. Formalin-fixed, paraffin-embedded tissue was immunostained with antibodies to p53, p27, phospho-AKT, and bcl-2 using the avidin-biotin-peroxidase method and tissue microarray technique. Tumors were assigned a positive or negative score based on more than 10% of tumor cells staining positive with the antibody. The subtypes of NSCLC included 48 adenocarcinomas, 47 squamous cell carcinomas, and 10 large cell undifferentiated carcinomas. A total of 54 tumors were pathologic stage I, 23 were stage II, and 26 were stage III. All subjects smoked (range, 10-175 pack-years; mean, 60 pack-years). The mean overall survival was 112 weeks (median, 129 weeks). Patients with p53-positive tumors had significantly fewer pack-years of smoking (52 pack-years vs 72 pack-years; P = 0.021), smoked fewer years (34 years vs 40 years; P = 0.018), and had significantly better survival compared with those with p53-negative tumors (P = 0.045). When smoking history was further analyzed, the authors found that p53 expression was associated with the number of years smoked and not the number of packs smoked per day. Patients with squamous cell carcinoma had smoked longer compared with those with adenocarcinoma (P = 0.011). Significant association was seen between the CYP2E1 wild-type allele and better survival (P = 0.016). Patients with stage I tumors had better survival compared with stages II and III (P = 0.032). No association was found between survival and tumor type; tumor differentiation; expression of phospho-AKT, p27, and bcl-2; and polymorphic metabolizing genes other than CYP2E1. The significant association of long duration of smoking (>40 years) with loss of p53 expression and poor survival suggests inactivation of the protective p53 pathway in those who had a history of more than 40 years of smoking.
Appl Immunohistochem Mol Morphol 2004 Dec
PMID:CYP2E1 polymorphism, cigarette smoking, p53 expression, and survival in non-small cell lung cancer: a long term follow-up study. 1553 30


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