Maintenance of adenomatous polyposis coli (APC)-mutant colorectal cancer is dependent on Wnt/beta-catenin signaling.

Abstract

Persistent expression of certain oncogenes is required for tumor maintenance. This phenotype is referred to as oncogene addiction and has been clinically validated by anticancer therapies that specifically inhibit oncoproteins such as BCR-ABL, c-Kit, HER2, PDGFR, and EGFR. Identifying additional genes that are required for tumor maintenance may lead to new targets for anticancer drugs. Although the role of aberrant Wnt pathway activation in the initiation of colorectal cancer has been clearly established, it remains unclear whether sustained Wnt pathway activation is required for colorectal tumor maintenance. To address this question, we used inducible β-catenin shRNAs to temporally control Wnt pathway activation in vivo. Here, we show that active Wnt/β-catenin signaling is required for maintenance of colorectal tumor xenografts harboring APC mutations. Reduced tumor growth upon β-catenin inhibition was due to cell cycle arrest and differentiation. Upon reactivation of the Wnt/β-catenin pathway colorectal cancer cells resumed proliferation and reacquired a crypt progenitor phenotype. In human colonic adenocarcinomas, high levels of nuclear β-catenin correlated with crypt progenitor but not differentiation markers, suggesting that the Wnt/β-catenin pathway may also control colorectal tumor cell fate during the maintenance phase of tumors in patients. These results support efforts to treat human colorectal cancer by pharmacological inhibition of the Wnt/β-catenin pathway.

• Authors: Alix Scholer-Dahirel, Michael R Schlabach, Alice Loo, Linda Bagdasarian, Ronald Meyer, Ribo Guo, Steve Woolfenden, Kristine K Yu, Judit Markovits, Karen Killary, Dmitry Sonkin, Yung-Mae Yao, Markus Warmuth, William R Sellers, Robert Schlegel, Frank Stegmeier, Rebecca E Mosher, Margaret E McLaughlin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 41 Pg. 17135-40 (Oct 11 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21949247 (Publication Type: Journal Article)

Chemical References

• CTNNB1 protein, human
• RNA, Small Interfering
• beta Catenin

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Cell Cycle
• Cell Differentiation
• Cell Line, Tumor
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Genes, APC
• Humans
• Mice
• Mice, Nude
• Mutation
• Neoplasm Transplantation
• RNA, Small Interfering (genetics)
• Signal Transduction
• Transplantation, Heterologous
• Wnt Signaling Pathway
• beta Catenin (antagonists & inhibitors, genetics, metabolism)