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Treatment of Radioresistant Stem-Like Esophageal Cancer Cells by an Apoptotic Gene-Armed, Telomerase-Specific Oncolytic Adenovirus

Authors' Affiliations: Departments of ¹ Radiation Oncology and ² Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Joe Y. Chang, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-2337; Fax: 713-563-2331; E-mail: jychang{at}mdanderson.org.

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 β-catenin, Oct3/4, and β₁ 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.