Met receptor signaling: a key effector in esophageal adenocarcinoma.
OBJECTIVE
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.


METHODS
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/beta-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 beta-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/beta-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.
Anderson
Mark R
MR
Department of Clinical Pharmacology, Oxford University, Oxford, United Kingdom. markanderson55@hotmail.com
Harrison
Rebecca
R
Atherfold
Paul A
PA
Campbell
Moray J
MJ
Darnton
S Jane
SJ
Obszynska
Jolanta
J
Jankowski
Janusz A Z
JA
D000230:Adenocarcinoma / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology*; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D017931:DNA Primers; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology*; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D015994:Incidence; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics*; D015398:Signal Transduction
D015820:Cadherins; D017931:DNA Primers; C066855:HGF protein, human; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met