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The suppression of colon cancer cell growth in nude mice by targeting beta-catenin/TCF pathway
Ka Yin Kwong1, Yiyu Zou, Chi-Ping Day
1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Abstract:
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.
Insights
This study developed a gene therapy using AdTOP-CMV-TK to target colorectal cancer cells with activated beta-catenin. The treatment effectively suppressed tumor growth in animal models, showing therapeutic potential.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Colorectal cancers frequently harbor mutations in adenomatous polyposis coli (APC) or beta-catenin genes.
- Mutations lead to activation of the beta-catenin/T-cell factor (Tcf) pathway, driving downstream gene expression.
Purpose of the Study:
- To develop and evaluate a gene therapy approach for selectively targeting colorectal cancer cells with an activated beta-catenin/Tcf4 pathway.
- To assess the therapeutic efficacy of AdTOP-CMV-TK and ganciclovir (GCV) in preclinical models.
Main Methods:
- Development of a recombinant adenovirus (AdTOP-CMV-TK) containing the herpes simplex virus thymidine kinase (HSV TK) gene.
- The HSV TK gene is under the control of a beta-catenin/Tcf-response promoter linked to a minimum CMV promoter.
- Treatment of human DLD-1 colon cancer cells and human hepatoma cell line SK-HEP-1 (control) in nude mice with AdTOP-CMV-TK and GCV.
Main Results:
- AdTOP-CMV-TK and GCV treatment significantly suppressed the growth of human DLD-1 colon cancer cells in nude mice.
- No significant tumor suppression was observed in the SK-HEP-1 cell line, where the beta-catenin/Tcf pathway is not activated, confirming selective targeting.
- Demonstrated selective targeting of colorectal cancers with activated beta-catenin in animal models.
Conclusions:
- The AdTOP-CMV-TK and GCV treatment strategy effectively targets colorectal cancers with activated beta-catenin.
- This approach shows therapeutic potential for colon cancer, including liver metastases.
