Inhibition of the EGFR and hedgehog signaling pathways demonstrate potent growth inhibition in an animal model of esophageal carcinogenesis

摘要: Abstract Introduction. Advancements in experimental therapeutics for esophageal cancers have been hampered by the lack of a reliable preclinical model that recapitulates biology human cancer, including vivo growth and metastases. Methods. Bilious reflux was induced esophago-jejunostomy Sprague-Dawley rats. Eight nine SD rats developed squamous or adenosquamous cancers, three new cell lines were created vitro propagation, JA JB from one, AMY line other. We subsequently tested ability these to propagate long-term form tumors vivo. In addition, we determined effects small molecule inhibitors two important oncogenic pathways---the epidermal factor receptor (EGFR) hedgehog (Hh) signaling pathways, vitro. Relative inhibition measured as described (Berman et al Nature 2003) at 48 96 h, using standard MTS assay. Results. JA, JB, are able grow continuously vitro, with consistent athymic mice, both subcutaneous xenografts orthotopically implanted gastroesophageal serosa (N = 2 mice per line, six engrafted each). By histology, well-differentiated keratinizing carcinomas. Iressa (gefitinib), an EGFR inhibitor (5 μm), caused significant all (JA > AMY) compared mock-treated cells, mirrored functionally down regulation activated targets pathway, phospho-ERK1/2, phospho-MEK levels, EGFR-inhibited cells. Cyclopamine, Hh pathway antagonist (dose 6 but not lines; accompanied reporter activity 24 h cells lines, specific antagonism pathway. Conclusions. established carcinogenesis, passage exhibiting pathway-specific antagonistic effects.