title: 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.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Alix
authors.initials: A
authors.lastname: Scholer-Dahirel
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schlabach
authors.forename: Alice
authors.initials: A
authors.lastname: Loo
authors.forename: Linda
authors.initials: L
authors.lastname: Bagdasarian
authors.forename: Ronald
authors.initials: R
authors.lastname: Meyer
authors.forename: Ribo
authors.initials: R
authors.lastname: Guo
authors.forename: Steve
authors.initials: S
authors.lastname: Woolfenden
authors.forename: Kristine K
authors.initials: KK
authors.lastname: Yu
authors.forename: Judit
authors.initials: J
authors.lastname: Markovits
authors.forename: Karen
authors.initials: K
authors.lastname: Killary
authors.forename: Dmitry
authors.initials: D
authors.lastname: Sonkin
authors.forename: Yung-Mae
authors.initials: YM
authors.lastname: Yao
authors.forename: Markus
authors.initials: M
authors.lastname: Warmuth
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Mosher
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McLaughlin
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017491:Genes, APC; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D034741:RNA, Small Interfering; D051176:beta Catenin