Treatment of Radioresistant Stem-like Esophageal Cancer Cells by an Apoptotic Gene-armed, Telomerase-specific Oncolytic Adenovirus

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2008 May 3

PMID 18451249

Citations 52

Authors

Xiaochun Zhang

Ritsuko Komaki

Li Wang

Bingliang Fang

Joe Y Chang

Affiliations

Soon will be listed here.

Abstract

Purpose: Radioresistance may be caused by cancer stem cells (CSC). Because CSCs require telomerase to proliferate, a telomerase-specific oncolytic adenoviral vector carrying apoptotic tumor necrosis factor-related apoptosis-inducing ligand and E1A gene (Ad/TRAIL-E1) may preferentially target CSCs.

Experimental Design: We established two pairs of parental and radioresistant (R) esophageal carcinoma cell lines (Seg-1, Seg-1R and TE-2, TE-2R) by fractionated irradiation. Stem cell markers were measured by Western blotting and flow cytometry. Serial sorting was used to enrich stem-like side population cells. Telomerase activity, transgene expression, antitumor activity, apoptosis induction, and viral replication were determined in vitro and/or in vivo.

Results: Expression of the stem cell markers beta-catenin, Oct3/4, and beta(1) integrin in Seg-1R cells was 29.4%, 27.5%, and 97.3%, respectively, compared with 4.8%, 14.9%, and 45.3% in Seg-1 cells (P < 0.05). SP levels in Seg-1R and TE-2R cells were 14.6% and 2.7%, respectively, compared with 3.4% and 0.3% in Seg-1 and TE-2 cells. Serial sorting of Seg-1R SP cells showed enrichment of the SP cells. Telomerase activities in Seg-1R, Seg-1R SP, and TE-2R cells were significantly higher than in Seg-1, Seg-1R non-SP, and TE-2 cells, respectively (P < 0.05). Seg-1R and TE-2R cells were more sensitive to Ad/TRAIL-E1 than parental cells. Increased Coxsackie-adenovirus receptor and elevated transgene expressions were found in the radioresistant cells. Ad/TRAIL-E1 resulted in significant tumor growth suppression and longer survival in Seg-1R-bearing mice (P < 0.05) with no significant toxicity.

Conclusion: Radioresistant cells established by fractionated irradiation display CSC-like cell properties. Ad/TRAIL-E1 preferentially targets radioresistant CSC-like cells.

Citing Articles

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The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells.

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Induction and assessment of persistent radioresistance in murine leukocytes .

Morales-Ramirez P, Cruz-Vallejo V, Vallarino-Kelly T, Rodriguez-Reyes R, Gonzalez-Beltran F Biochem Biophys Rep. 2022; 31:101296.

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