The suppression of colon cancer cell growth in nude mice by targetingβ-catenin/TCF pathway

Abstract

The adenomatous polyposis coli (APC) or β-catenin genes are frequently mutated in colorectal cancers, leading to activation of downstream genes with β-catenin/T-cell factor (Tcf)-responsive promoters. We have developed a gene therapy approach selectively targeting colorectal cancer cells in which β-catenin/Tcf4 pathway is activated by using a recombinant adenovirus AdTOP-CMV-TK, which carries a herpes simplex virus thymidine kinase gene (HSV TK) under the control of a β-catenin/Tcf-response promoter linking to a minimum CMV promoter. AdTOP-CMV-TK and ganciclovir (GCV) treatment significantly suppressed the growth of human DLD-1 colon cancer cells in nude mice. Furthermore, no significant tumor suppression effect was observed in human hepatoma cell line SK-HEP-1, in which the β-catenin/Tcf pathway is not activated, as a control experiment. In summary, we demonstrated the selective targeting of colorectal cancers with activated β-catenin by AdTOP-CMV-TK and GCV treatment in animal models, as well as its therapeutic potential for colon cancer metastasized to liver.