Thunnissen, F.B. (Frederick B.)

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    EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration. European Respiratory
    (European Respiratory Society, 2009-05-15) Pajares, M.J. (María José); Niklinski, J. (J.); Vignaud, J.M. (J.M.); Lozano, M.D. (María Dolores); EUELC; Niaz, A. (A.); Hainaut, P. (P.); Roz, L. (Luca); Vesin, A. (Aurelien); Liloglou, T. (Triantafillos); Elborn, J. (J.S.); Field, J.K. (J. K.); Prinsen, C. (C.); Gosney, J.R. (J. R.); Giles, T. (T.); Montuenga-Badia, L.M. (Luis M.); Brambilla, E. (E.); Sozzi, G. (Gabriella); Magee, N.D. (N.D.); Bryan, J. (J.); Cassidy, A. (A.); Thunnissen, F.B. (Frederick B.); Martinet, Y. (Y.); Risch, A. (A.); O'Byrne, K.J. (K.J.); Snijders, P.J. (P.J.); Harrison, D.J. (D. J.); Timsit, J.F. (J.F.); Becker, H. (H.D.); Smit, E.F. (E.F.); Brambilla, C. (C.)
    The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular–pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARb genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.
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    Mitogen-Activated Protein Kinase Phosphatase-1 Is Overexpressed in Non-Small Cell Lung Cancer and Is an Independent Predictor of Outcome in Patients
    (American Association for Cancer Research, 2004) Lozano, M.D. (María Dolores); Vicent, S. (Silvestre); Garayoa, M. (Mercedes); Toledo, G. (Gemma); Lopez-Picazo, J.M. (José M.); Montuenga-Badia, L.M. (Luis M.); Manzano, R.G. (Ramón G.); Thunnissen, F.B. (Frederick B.)
    An increase in the activity of the mitogen-activated protein kinases (MAPKs) has been correlated with a more malignant phenotype in several tumor models in vitro and in vivo. A key regulatory mechanism of the MAPKs [extracellular signal-regulated kinase (ERK); c-jun NH(2)-terminal kinase (JNK); and p38] is the dual specificity phosphatase CL100, also called MAPK phosphatase-1 (MKP-1). This study was designed to examine the involvement of CL100/MKP-1 and stress-related MAPKs in lung cancer. EXPERIMENTAL DESIGN: We assessed the expression of CL100/MKP-1 and the activation of the MAPKs in a panel of 18 human cell lines [1 primary normal bronchial epithelium, 8 non-small cell lung cancer (NSCLC), 7 small cell lung cancer (SCLC), and 2 carcinoids] and in 108 NSCLC surgical specimens. RESULTS: In the cell lines, CL100/MKP-1 expression was substantially higher in NSCLC than in SCLC. P-ERK, P-JNK, and P-p38 were activated in SCLC and NSCLC, but the degree of their activation was variable. Immunohistochemistry in NSCLC resection specimens showed high levels of CL100/MKP-1 and activation of the three MAPK compared with normal lung. In univariate analysis, no relationship was found among CL100/MKP-1 expression and P-ERK, P-JNK, or P-p38. Interestingly, high CL100/MKP-1 expression levels independently predicted improved survival in multivariate analysis. JNK activation associated with T(1-2) and early stage, whereas ERK activation correlated with late stages and higher T and N. Neither JNK nor ERK activation were independent prognostic factors when studied for patient survival. CONCLUSIONS: Our data indicate the relevance of MAPKs and CL100/MKP-1 in lung cancer and point at CL100/MKP-1 as a potential positive prognostic factor in NSCLC. Finally, our study supports the search of new molecular targets for lung cancer therapy within the MAPK signaling pathway.