Abstract
BackgroundIn intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Eph B3 in esophageal adenocarcinoma we analyzed the simultaneous expression of Eph B3 and E-cadherin in both the healthy esophagus and in Barrett’s carcinoma.MethodsSimultaneous expression of Eph B3 and E-cadherin was investigated in samples from 141 patients with Barrett’s carcinoma and from 20 healthy esophagi using immunhistology and quantitative PCR. Results from healthy squamous epithelium, Barrett’s metaplasia and staging-specific esophageal adenocarcinoma were correlated.ResultsA significantly reduced E-cadherin mRNA expression could be detected in adenocarcinoma compared to dysplasia. The immunhistological activity of E-cadherin and Eph B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when the Eph receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Eph B3 showed a significant inverse correlation to tumor stage.ConclusionsWe present novel evidence of the tumor suppressor activity of Eph B3 in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma sequence, the infiltrative growth pattern and the development of lymph node metastases.
Highlights
In intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1
Lymph node metastases are a strong predictor for a dismal long-term survival, which is reflected in our survival analysis with a five-year survival rate of patients with involved lymph nodes of 50% (P = 0.01)
In our patient group we show by quantitative Polymerase chain reaction (PCR) a significant reduction of E-cadherin expression in adenocarcinoma compared to Barrett’s metaplasia
Summary
Tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. Esophageal adenocarcinoma is a very aggressive cancer with a dismal five-year overall survival rate of only 20% [1,2,3]. These poor survival rates are due to the advanced stage of esophageal cancer at the time of diagnosis [3,4,5]. Even patients with early disease (for example, with a T1b-category) have lymph node metastases in up to 20% of the cases. This is known to be a strong prognostic. In the nervous system and the gastrointestinal tract, Ephrin receptor tyrosine kinases and their ligands, the ephrins, conduct axon guidance, development and cell intermingling [10].
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