1. Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer.
- Author
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Micke P, Mattsson JS, Edlund K, Lohr M, Jirström K, Berglund A, Botling J, Rahnenfuehrer J, Marincevic M, Pontén F, Ekman S, Hengstler J, Wöll S, Sahin U, and Türeci O
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma pathology, Aged, Biomarkers, Tumor genetics, Bronchi metabolism, Carcinoma, Large Cell genetics, Carcinoma, Large Cell pathology, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Claudins genetics, Female, Follow-Up Studies, Gene Expression Profiling, Humans, Immunoenzyme Techniques, Lung Neoplasms genetics, Lung Neoplasms pathology, Male, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Prognosis, Protein Isoforms, Tissue Array Analysis, Adenocarcinoma metabolism, Biomarkers, Tumor metabolism, Carcinoma, Large Cell metabolism, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Squamous Cell metabolism, Claudins metabolism, Lung Neoplasms metabolism
- Abstract
Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n = 355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n = 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho = 0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p = 0.03] and multivariate COX regression model (HR: 1.9; p = 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC., (© 2014 UICC.)
- Published
- 2014
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