For decades, hundreds of different human tumor type-specific cell lines have been used in experimental cancer research as models for their respective tumors. The veracity of experimental results for a specific tumor type relies on the correct derivation of the cell line. In a worldwide effort, we verified the authenticity of all available esophageal adenocarcinoma (EAC) cell lines. We proved that the frequently used cell lines SEG-1 and BIC-1 and the SK-GT-5 cell line are in fact cell lines from other tumor types. Experimental results based on these contaminated cell lines have led to ongoing clinical trials recruiting EAC patients, to more than 100 scientific publications, and to at least three National Institutes of Health cancer research grants and 11 US patents, which emphasizes the importance of our findings. Widespread use of contaminated cell lines threatens the development of treatment strategies for EAC.

Barrett's metaplasia (BM) is an early lesion in the progression from oesophageal inflammation through dysplasia to the development of Barrett's adenocarcinoma (BA). Previous work indicates that BM and BA are associated with reduced E-cadherin expression and increased cytoplasmic/nuclear pools of its associated protein b-catenin. b-catenin participates in Wnt signalling and activates oncogene transcription by complexing with T-cells factors (TCF). One such oncogene is c-myc. We have previously shown that TNF-a can downregulate E-cadherin expression. Here, we assess TNF-a expression in Barrett's metaplasia and examine if TNF-a can promote b-catenin mediated transcription of oncogenes in a gastrointestinal model system. Employing immunohistochemistry and Western blot analysis of oesophageal tissue, epithelial expression of TNF-a increases with progression along the metaplasia -dysplasia -carcinoma sequence (P50.001). b-catenin mediated transcription was then assessed in TNF-a stimulated cell lines using the TOPFLASH reporter system whilst cmyc expression was assessed by real time PCR. In a columnar intestinal cell model, TNF-a induces c-myc expression which is induced via b-catenin mediated transcription (P50.05). This b-catenin mediated transcription is independent of NF-kB activation. Thus, TNF-a is up-regulated in the progression of Barrett's oesophagus and b-catenin mediated transcription of cmyc is a novel pathway whereby elevated levels of TNF-a may lead to oncogene transcription and altered biology in gastrointestinal epithelia and metaplasia.

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We conclude that p53 alterations (mutations and/or protein overexpression) are a predictor of reduced postoperative survival after surgical resection of esophageal adenocarcinomas and that p53 may be a clinically useful molecular marker for stratifying patients in future clinical trials. Patterns of p53 mutations suggest endogenous mutational mechanisms.