title: Insulin-like growth factor-1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus.
abstract: Insulin-like growth factor-1 receptor (IGF-1R) and human epidermal growth factor receptor-2 (HER2) receptor expression has been found to be a key regulator of tumorigenesis. The purpose of our study was to establish the prognostic significance of IGF-1R in esophageal cancer and to determine the effect of IGF-1R and HER2 targeting with alpha-IR3 and Herceptin antibodies on the proliferation of esophageal cancer cells in vitro. IGF-1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens (133 adenocarcinomas and 101 squamous cell carcinomas). Proliferation changes associated with Herceptin and alpha-IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590. IGF-1R and HER2 expression levels, activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting. IGF-1R overexpression was detected in 121 (52%) of the 234 esophageal tumors examined. In the subgroup of 87 HER2-positive tumors, 93.1% showed concordant overexpression for IGF-1R. IGF-1R was identified as a variable associated with reduced overall survival for adenocarcinoma (p = 0.05), but not for squamous cell carcinoma. The combination of Herceptin and alpha-IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone (p < 0.01). This was associated with a decrease in HER2 and IGF-1R protein levels and suppression of Akt- and MAP kinase phosphorylation. IGF-1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus. Cotreatment with IGF-1R and HER2 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma.
authors.affiliation: Department of General, Visceral- and Thoracic Surgery, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Kalinina
authors.forename: Maximilian
authors.initials: M
authors.lastname: Bockhorn
authors.forename: Jussuf T
authors.initials: JT
authors.lastname: Kaifi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Thieltges
authors.forename: Cenap
authors.initials: C
authors.lastname: Güngör
authors.forename: Katharina E
authors.initials: KE
authors.lastname: Effenberger
authors.forename: Andrea
authors.initials: A
authors.lastname: Strelow
authors.forename: Uta
authors.initials: U
authors.lastname: Reichelt
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.forename: Emre F
authors.initials: EF
authors.lastname: Yekebas
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab; C508053:ERBB2 protein, human