Journal article
Adenoma Formation following Limited Ablation of p120-Catenin in the Mouse Intestine
PloS one, Vol.6(5), pp.e19880-e19880
05/17/2011
DOI: 10.1371/journal.pone.0019880
PMCID: PMC3096651
PMID: 21611205
Abstract
p120 loss destabilizes E-cadherin and could therefore result in tumor and/or metastasis-promoting activities similar to those caused by E-cadherin downregulation. Previously, we reported that p120 is essential in the intestine for barrier function, epithelial homeostasis and survival. Conditional p120 ablation in the mouse intestine induced severe inflammatory bowel disease, but long-term cancer-related studies were impossible because none of the animals survived longer than 21 days. Here, we used a tamoxifen-inducible mouse model (Vil-Cre-ER
T2
;p120
fl/fl
) to limit the extent of p120 ablation and thereby enable long-term studies. Reducing p120 KO to ∼10% of the intestinal epithelium produced long-lived animals outwardly indistinguishable from controls. Effects of prolonged p120 absence were then evaluated at intervals spanning 2 to 18 months. At all time points, immunostaining revealed microdomains of p120-null epithelium interspersed with normal epithelium. Thus, stochastic p120 ablation is compatible with crypt progenitor cell function and permitted lifelong renewal of the p120-null cells. Consistent with previous observations, a barrier defect and frequent infiltration of neutrophils was observed, suggesting that focal p120 loss generates a microenvironment disposed to chronic inflammation. We report that 45% of these animals developed tumors within 18 months of tamoxifen induction. Interestingly, β-catenin was upregulated in the majority, but none of the tumors were p120 null. Although further work is required to directly establish mechanism, we conclude that limited p120 ablation can promote tumorigenesis by an indirect non-cell autonomous mechanism. Given that byproducts of inflammation are known to be highly mutagenic, we suggest that tumorigenesis in this model is ultimately driven by the lifelong inability to heal chronic wounds and the substantially increased rates of stochastic gene mutation in tissue microenvironments subjected to chronic inflammation. Indeed, although technical issues precluded direct identification of mutations, β-catenin upregulation in human colon cancer almost invariably reflects mutations in APC and/or β-catenin.
Details
- Title: Subtitle
- Adenoma Formation following Limited Ablation of p120-Catenin in the Mouse Intestine
- Creators
- Whitney G. Smalley-Freed - Vanderbilt UniversityAndrey Efimov - Vanderbilt UniversitySarah P. Short - Vanderbilt UniversityPeilin Jia - Vanderbilt UniversityZhongming Zhao - Vanderbilt UniversityM. Kay Washington - Northwestern UniversitySylvie Robine - Institut CurieRobert J. Coffey - Vanderbilt UniversityAlbert B. Reynolds - Northwestern University
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.6(5), pp.e19880-e19880
- DOI
- 10.1371/journal.pone.0019880
- PMID
- 21611205
- PMCID
- PMC3096651
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library of Science
- Alternative title
- p120 KO and Tumorigenesis in the Mouse Intestine
- Language
- English
- Date published
- 05/17/2011
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984420841702771
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