title: Immunohistochemical analysis on potential new molecular targets for esophageal cancer.
abstract: Despite multimodal therapeutic options, esophageal cancer is still among the most deadly malignancies. In the past decade, targeted therapy has shown great potential in other cancers, but data on esophageal carcinoma are still rare. Five potential new molecular targets in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) were investigated for their expression characteristics: vascular endothelial growth factor receptor (VEGFR)-3, human epidermal growth factor receptor-2, stem cell growth factor receptor, tissue inhibitors of metalloproteinase (TIMP)-4 and TIMP-3. One hundred seventy-one EAC and ESCC tissue samples obtained from patients undergoing esophagectomy from 2000 to 2008 were included. Clinical data were evaluated retrospectively. Immunohistochemical staining was performed using tumor tissue with and without neoadjuvant treatment and healthy tissue. For samples without neoadjuvant treatment, expression of all targets was higher in tumor tissue than in healthy tissue except for VEGFR-3 (>98% expression in both tissues). For TIMP-4, TIMP-3 and stem cell growth factor receptor, trends to higher expression in tumor tissue were also found in EAC and ESCC that had received neoadjuvant treatment. Using Matched-pair analysis, we compared target expression in tumor tissue with and without neoadjuvant treatment. Only TIMP-3 had significantly lower expression in neoadjuvant treated tumor tissue (EAC: P = 0.059, ESCC: P = 0.006). TIMP-4, TIMP-3 and VEGFR-3 appear to qualify for targeted therapy in esophageal cancer because of their high expression in neoplastic tissue. TIMP-3 appears to be downregulated in neoadjuvantly treated esophageal cancer, and VEGFR-3 shows high expression in healthy mucosa leading to severe side effects by molecular targeting. Thus, TIMP-4 seems the most promising target.
authors.affiliation: Department of General and Visceral Surgery, University of Muenster, Muenster, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Maurer
authors.forename: M
authors.initials: M
authors.lastname: Schöpp
authors.forename: K
authors.initials: K
authors.lastname: Thurau
authors.forename: J
authors.initials: J
authors.lastname: Haier
authors.forename: G
authors.initials: G
authors.lastname: Köhler
authors.forename: R
authors.initials: R
authors.lastname: Hummel
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000628:therapy; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000628:therapy; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000628:therapy; D016629:Esophagectomy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit; D018719:Erb-b2 Receptor Tyrosine Kinases; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D040321:Vascular Endothelial Growth Factor Receptor-3; D000097792:Tissue Inhibitor of Metalloproteinase-4; C088390:TIMP3 protein, human; C508053:ERBB2 protein, human; C581309:FLT4 protein, human
keywords: Her2/neu; TIMP; VEGFR-3; esophageal cancer; immunohistochemistry; molecular targeted therapy