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Met Receptor Signaling: A Key Effector in Esophageal Adenocarcinoma

Authors' Affiliations: ¹ Department of Clinical Pharmacology, Oxford University, Oxford, United Kingdom; ² Digestive Diseases Centre, University Hospitals of Leicester, Leicester, United Kingdom; ³ University of Birmingham; ⁴ Birmingham Heartlands Hospital, Birmingham, United Kingdom; and ⁵ London Research Institute, Cancer Research UK, London, United Kingdom

Requests for reprints: Mark R. Anderson, Department of Gastroenterology, City Hospital, Dudley Road, Birmingham, B18 7QH, United Kingdom. Phone: 44-121-507-4589; Fax: 44-121-507-5665; E-mail: markanderson55{at}hotmail.com.

Purpose: The incidence of esophageal adenocarcinoma is rising, and survival rates remain poor. The hepatocyte growth factor (HGF) receptor Met has been detected in esophageal cancer. The perturbation of cadherin/catenin complexes has also been shown. We sought to investigate a link among Met expression, cadherin/catenin biology, and cell growth. We assessed the prognostic significance of Met expression in esophageal adenocarcinoma.

Experimental Design: Met and HGF expression in esophageal tissues were assessed using immunohistochemistry and ELISA. Met-positive cell lines (OE33 and SEG1) and a Met-negative cell line (TE7) were incubated with HGF. Real-time reverse transcription-PCR and Western blotting were used to assess levels of E-cadherin expression. Nuclear TCF/ß-catenin signaling was assessed following reporter construct transfection. Agar colony formation was used to assess anchorage-independent growth. A panel of 72 resected esophageal adenocarcinomas were assessed for Met expression by immunohistochemistry and correlated to survival data.

Results: An increased expression of Met was seen along the metaplasia- adenocarcinoma sequence. Met-positive cells showed reductions in E-cadherin mRNA (37% and 69%) and protein expression following stimulation with HGF (P < 0.01). OE33 and SEG-1 showed up to a 2-fold increase in the levels of ß-catenin nuclear signaling (P < 0.01). TE7 only responded when transfected to express Met; E-cadherin expression decreased by 64% (P < 0.01). HGF stimulation led to increased agar colony formation (P < 0.01). Patients with Met-positive tumors showed lower 6-month survival rates after surgical resection than those with Met-negative tumors (P < 0.05).

Conclusions: Met activation induces changes consistent with early invasion, such as down-regulation of E-cadherin, increased nuclear TCF/ß-catenin signaling, and anchorage-independent growth. This is supported by ex vivo data associating Met with reduced short-term survival. Inhibitors of Met may be effective treatment for esophageal adenocarcinoma.

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