Maintenance of adenomatous polyposis coli ( APC )-mutant colorectal cancer is dependent on Wnt/β-catenin signaling
- 23 September 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 108 (41), 17135-17140
- https://doi.org/10.1073/pnas.1104182108
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.Keywords
This publication has 30 references indexed in Scilit:
- Colorectal Tumors Are Effectively Eradicated by Combined Inhibition of β-Catenin, KRAS, and the Oncogenic Transcription Factor ITF2Cancer Research, 2010
- Specific inhibition of gene expression using a stably integrated, inducible small‐interfering‐RNA vectorEMBO Reports, 2003
- Small interfering RNAs directed against beta-catenin inhibit the in vitro and in vivo growth of colon cancer cells.2003
- Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoterOncogene, 2003
- The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer CellsCell, 2002
- Casein Kinase 1: A Wnt'er of DisconnectCurrent Biology, 2002
- Targeted inactivation of CTNNB1 reveals unexpected effects of β-catenin mutationProceedings of the National Academy of Sciences of the United States of America, 2002
- Coordinating cell proliferation and differentiationCurrent Opinion in Genetics & Development, 2001
- Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signallingNature Genetics, 2000
- Intestinal polyposis in mice with a dominant stable mutation of the beta -catenin geneThe EMBO Journal, 1999