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E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models

Abstract

The thymidine kinase/ganciclovir (TK/GCV) cancer gene therapy approach is based on inducing GCV metabolite cytotoxicity in tumor cells expressing the herpes simplex virus TK gene and exposed to GCV. A bystander effect, mediated by gap junctions, accounts for the transfer of toxic metabolites from TK-expressing cells to neighboring cells. It has been proposed that E-cadherin participates in the formation and function of such gap junctions. In this study we investigate the influence of E-cadherin on TK/GCV suicide therapy with a panel of cellular and in vivo models of pancreatic ductal adenocarcinoma. We observed a strong correlation of E-cadherin expression and the TK/GCV bystander effect, associated with the modulation of gap junction communication and connexin expression or localization. Importantly, the co-expression of TK and E-cadherin genes in the adenoviral vector AdTat8TKIE improved TK/GCV cytotoxicity and triggered a potent antitumoral effect, superior to standard AdTat8TK/GCV in MIAPaCa-2 xenografts. The increased expression of E-cadherin resulted in the reduction of the bcl-2 content. Interestingly, the knockdown of bcl-2 sensitized cells to TK/GCV. Thus, we propose that by restoring E-cadherin in pancreatic tumor cells we will improve TK/GCV therapy, both by enhancing the bystander effect and by facilitating the induction of apoptosis.

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Acknowledgements

We thank Anna Cascante for the generation of the pBabeEcad retroviral vector. The pAVU6+27 was kindly provided by Dr Albert Jordan. This work was supported by the Spanish Ministry of Education and Science, BIO2005-08682-C03-02, BIO2008-04692-C03-02 and received partial support from the Generalitat de Catalunya (SGR0500008 and SGR091527). Laura Garcia-Rodríguez was a recipient of a fellowship (FI) granted by the Generalitat de Catalunya—European Social Fund. C Fillat's group was also partially funded by CIBERER, Instituto de Salud Carlos III.

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Garcia-Rodríguez, L., Abate-Daga, D., Rojas, A. et al. E-cadherin contributes to the bystander effect of TK/GCV suicide therapy and enhances its antitumoral activity in pancreatic cancer models. Gene Ther 18, 73–81 (2011). https://doi.org/10.1038/gt.2010.114

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