Met Receptor Signaling: A Key Effector in Esophageal Adenocarcinoma

• Published in: Clinical cancer research Vol. 12; no. 20; pp. 5936 - 5943
• Main Authors: ANDERSON, Mark R, HARRISON, Rebecca, ATHERFOLD, Paul A, CAMPBELL, Moray J, DARNTON, S. Jane, OBSZYNSKA, Jolanta, JANKOWSKI, Janusz A. Z
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2006
• Subjects: Adenocarcinoma - epidemiology; Adenocarcinoma - pathology; Adenocarcinoma - physiopathology; Antineoplastic agents; Barrett's metaplasia; Base Sequence; Biological and medical sciences; Cadherin; Cadherins - genetics; Cell Line, Tumor; DNA Primers; Esophageal adenocarcinoma; Esophageal Neoplasms - epidemiology; Esophageal Neoplasms - pathology; Esophageal Neoplasms - physiopathology; Esophagus; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor - genetics; Humans; Incidence; Medical sciences; Met; Pharmacology. Drug treatments; Polymerase Chain Reaction; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-met; Receptors, Growth Factor - genetics; Signal Transduction; Tumors; Signaling pathway; C-Onc gene; Esophageal disease; Digestive diseases; Esophagus adenocarcinoma; Malignant tumor; Effector; Esophagus cancer; Protooncogene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-1208

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/β-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 β-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/β-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.