Abstract
Abstract The overall long-term survival for patients with esophageal adenocarcinoma (EAC) remains poor. Despite improved understanding of the progression from Barrett's esophagus to dysplasia to adenocarcinoma, patients commonly present with advanced stage disease and demonstrate resistance to conventional therapy, with response rates below 40%. Understanding the molecular mechanisms of resistance is crucial for predicting and overcoming this resistance. Twenty EAC tissues obtained from patients subsequently treated with chemotherapy were examined using Affymetrix oligonucleotide microarrays. Genes differentially expressed in disease-free patients compared to patients with recurrent disease were identified. One such gene, insulin-like growth factor binding protein-2 (IGFBP-2), is a member of the IGF signaling pathway, which has been shown to play pivotal roles in cell growth, differentiation, survival, transformation, and metastasis. Increased IGFBP-2 expression has been reported in many advanced tumor types and has been previously linked to chemoresistance, making it a promising potential target in EAC. Mean IGFBP-2 levels were significantly higher in patients with recurrent disease and increased expression was associated with worse outcome independent of stage. Of three EAC cell lines examined (Flo-1, OE33, OE19), Flo-1 cells showed the highest IGFBP-2 expression at both the mRNA and protein levels. To examine the role of IGFBP-2 in chemoresistance, Flo-1 cells were pre-treated with siRNA to IGFBP-2 followed by chemotherapy in the presence or absence of serum and analyzed using WST-1 cell proliferation assays. Knocking down IGFBP-2 sensitized Flo-1 cells to cisplatin in the presence of serum and increased proliferation in serum-free conditions, suggesting that IGFBP-2 may be anti-proliferative in this EAC cell line. In addition, treatment of Flo-1 cells with both acute and chronic doses of cisplatin decreased expression of IGFBP-2. Stable transfection of IGFBP-2 into low-level IGFBP-2-expressing OE33 and OE19 cells did not alter cellular proliferation/chemosensitivity, migration, or epithelial-mesenchymal transition as determined by WST-1, wound healing, and Western analyses, respectively, possibly due to amplification of the ErbB2 gene in these cell lines. Although preliminary data suggest that IGFBP-2 may mediate chemoresistance in EAC, its effects may be masked by more potent genetic alterations. Further analysis of the IGF signaling pathway is warranted to determine its significance in the chemoresistance of EAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 830. doi:1538-7445.AM2012-830
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call