Details

Autor(en) / Beteiligte

• Scholer-Dahirel, Alix
• Schlabach, Michael R
• Loo, Alice
• Bagdasarian, Linda
• Meyer, Ronald
• Guo, Ribo
• Woolfenden, Steve
• Yu, Kristine K
• Markovits, Judit
• Killary, Karen
• Sonkin, Dmitry
• Yao, Yung-Mae
• Warmuth, Markus
• Sellers, William R
• Schlegel, Robert
• Stegmeier, Frank
• Mosher, Rebecca E
• McLaughlin, Margaret E

Titel

Maintenance of adenomatous polyposis coli (APC)-mutant colorectal cancer is dependent on Wnt/[Beta]-catenin signaling

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2011-10, Vol.108 (41), p.17135

Ort / Verlag

Washington: National Academy of Sciences

Erscheinungsjahr

2011

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. [PUBLICATION ABSTRACT]