1. ¹Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA
2. ²Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
3. ³Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
4. ⁴Department of Oncology, London Regional Cancer Center, London, Ontario, Canada

Correspondence: Dr DG Beer, Department of Surgery, Section of General Thoracic Surgery, MSRB II B560, Box 0686, University of Michigan Medical School, Ann Arbor, MI 48109, USA. E-mail: dgbeer@umich.edu

⁵These authors contributed equally to this work

Received 10 March 2005; Revised 27 July 2005; Accepted 27 July 2005; Published online 26 September 2005.

Abstract

Esophageal adenocarcinoma (EA) is characterized by a poor prognosis making the identification of clinically targetable proteins essential for improving patient outcome. We report the involvement of multiple alterations of the MET pathway in EA development and progression. Microarray analysis of Barrett's metaplasia, dysplasia, and EA revealed overexpression of the MET oncogene in EAs but only those with MET gene amplification. STS-amplification mapping revealed that the boundary of the MET amplicon in these EAs is defined by fragile site FRA7G. We also identified an amplicon at 11p13 that resulted in amplification and overexpression of CD44, a gene involved in MET autophosphorylation upon HGF stimulation. Tissue microarrays with phospho-MET-specific antibodies demonstrated a uniformly high abundance of MET activation in primary EA and cells metastatic to lymph nodes but to a lesser extent in a subset of metaplastic and dysplastic Barrett's samples. Increased expression of multiple genes in the MET pathway associated with invasive growth, for example, many MMPs and osteopontin, also was found in EAs. Treatment of EA-derived cell lines with geldanamycin, an inhibitor for tyrosine kinases including MET receptor kinase, reduced cell migration and induced EA cell apoptosis. The data indicate that upregulation of the MET pathway may contribute to the poor outcome of EA patients and that therapeutic agents targeting this pathway may help improve patient survival.