The suppression of colon cancer cell growth in nude mice by targeting beta-catenin/TCF pathway.
The adenomatous polyposis coli (APC) or beta-catenin genes are frequently mutated in colorectal cancers, leading to activation of downstream genes with beta-catenin/T-cell factor (Tcf)-responsive promoters. We have developed a gene therapy approach selectively targeting colorectal cancer cells in which beta-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 beta-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 beta-catenin/Tcf pathway is not activated, as a control experiment. In summary, we demonstrated the selective targeting of colorectal cancers with activated beta-catenin by AdTOP-CMV-TK and GCV treatment in animal models, as well as its therapeutic potential for colon cancer metastasized to liver.
Kwong
Ka Yin
KY
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Zou
Yiyu
Y
Day
Chi-Ping
CP
Hung
Mien-Chie
MC
D000818:Animals; D002455:Cell Division; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D003587:Cytomegalovirus / Q000201:enzymology / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D013937:Thymidine Kinase / Q000235:genetics; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D007376:Interleukin-2; D015534:Trans-Activators; D051176:beta Catenin; D013937:Thymidine Kinase