Abstract 2033: Transforming growth factor-b-induced epithelial-mesenchymal transition is attenuated by telomerase-specific oncolytic virotherapy in human esophageal cancer

Abstract

Abstract Background: Epithelial-mesenchymal transition (EMT) is known to be one of the poor prognostic factors. EMT is a biological process, by which epithelial cancer cells lose their epithelial characteristics and gain mesenchymal properties, including invasion, metastasis and drug resistance, resulting in tumor recurrence and poor prognosis. Esophageal cancer is one of the most common cause of cancer-related death worldwide, especially in East Asia. Despite the recent advances in the treatment of esophageal cancer, antitumor therapy to inhibit EMT program remains to be developed. We developed a telomerase-specific replication-selective oncolytic adenovirus (OBP-301; Telomelysin), in which the human telomerase reverse transcriptase promoter drives the expression of E1A and E1B for virus replication. In this study, we explored the biological effect of OBP-301 on EMT in human esophageal cancer cells. Methods: Transforming growth factor-β (TGF-β) was used to induce EMT in human esophageal cancer TE-4 cells. To investigate whether OBP-301 infection affects TGF-β-induced EMT, we performed western blot and real-time PCR analysis for EMT-related markers. We also examined the migration capability using transwell migration assay. In vitro antitumor effect of OBP-301 and chemotherapeutic agents on TGF-β-treated TE-4 cells were assessed by a XTT assay. Results: Administration of TGF-β induced mesenchymal characteristics, including spindle-shaped morphology, increased migration capability, and upregulation of mesenchymal markers N-cadherin and vimentin, in TE-4 cells. When TGF-β-treated TE-4 cells were infected with OBP-301, upregulation of N-cadherin and vimentin expression was attenuated. Upregulation of EMT-transcription factors, Snail, Slug, and ZEB1 by TGF-β was reduced by OBP-301 infection. OBP-301 also inhibited TGF-β-induced enhancement of migration capability. Moreover, interestingly, EMT-induced TE-4 cells acquired chemoresistance, whereas they were sensitive to OBP-301-mediated lytic effect. Conclusion: Our data suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to inhibit TGF-β-induced EMT and warrants clinical trials in human esophageal cancer. Currently, we are conducting a phase I/II clinical study of OBP-301 in combination with radiotherapy for esophageal cancer. Citation Format: Tomoya Masuda, Hiroshi Tazawa, Takeshi Ieda, Yuuri Hashimoto, Shunsuke Tanabe, Kazuhiro Noma, Yasuo Urata, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Transforming growth factor-b-induced epithelial-mesenchymal transition is attenuated by telomerase-specific oncolytic virotherapy in human esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2033.