title: Adenoma formation following limited ablation of p120-catenin in the mouse intestine.
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.
authors: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors: Whitney G
authors: WG
authors: Smalley-Freed
authors: Andrey
authors: A
authors: Efimov
authors: Sarah P
authors: SP
authors: Short
authors: Peilin
authors: P
authors: Jia
authors: Zhongming
authors: Z
authors: Zhao
authors: M Kay
authors: MK
authors: Washington
authors: Sylvie
authors: S
authors: Robine
authors: Robert J
authors: RJ
authors: Coffey
authors: Albert B
authors: AB
authors: Reynolds
references: Cancer Sci. 2008 Jul;99(7):1348-54
references: 18422752
references: Nature. 1998 Mar 12;392(6672):190-3
references: 9515965
references: Semin Cell Dev Biol. 2004 Dec;15(6):657-63
references: 15561585
references: Virchows Arch A Pathol Anat Histopathol. 1992;421(2):149-56
references: 1514246
references: Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8813-7
references: 7568023
references: J Gastroenterol Hepatol. 2002 Oct;17(10):1078-83
references: 12201867
references: Am J Pathol. 2006 Dec;169(6):1901-9
references: 17148655
references: J Clin Invest. 1996 Aug 15;98(4):1010-20
references: 8770874
references: Nature. 2002 Dec 19-26;420(6917):860-7
references: 12490959
references: Cancer Lett. 1998 Oct 23;132(1-2):193-201
references: 10397474
references: J Cell Biol. 1995 Jul;130(1):67-77
references: 7790378
references: Gut. 1996 Jul;39(1):87-92
references: 8881816
references: Cancer Cell. 2006 Nov;10(5):437-49
references: 17097565
references: Cell. 1991 May 31;65(5):849-57
references: 1904011
references: Inflamm Bowel Dis. 2009 Jul;15(7):997-1006
references: 19229991
references: Curr Opin Cell Biol. 2001 Oct;13(5):604-10
references: 11544030
references: Oncogene. 1996 Nov 7;13(9):1919-25
references: 8934538
references: J Cell Biol. 2003 Nov 10;163(3):525-34
references: 14610055
references: Cell. 2006 Feb 24;124(4):823-35
references: 16497591
references: Cell. 1991 Jul 12;66(1):107-19
references: 2070412
references: Science. 1995 Nov 17;270(5239):1203-7
references: 7502046
references: Cell. 2006 Feb 10;124(3):631-44
references: 16469707
references: J Cell Biol. 1991 Apr;113(1):173-85
references: 2007622
references: J Exp Med. 2007 Jun 11;204(6):1417-29
references: 17517967
references: Development. 2009 Mar;136(5):723-7
references: 19158184
references: Gastroenterology. 2007 Dec;133(6):2049-52
references: 18054577
references: Dev Cell. 2006 Jan;10(1):21-31
references: 16399075
references: Cell. 1998 Sep 18;94(6):703-14
references: 9753318
references: Mol Cancer Res. 2007 Apr;5(4):341-9
references: 17426249
references: Mol Pathol. 2002 Apr;55(2):80-2
references: 11950953
references: Curr Opin Cell Biol. 1995 Oct;7(5):619-27
references: 8573335
references: Nature. 2005 Jul 7;436(7047):123-7
references: 16001073
references: Gastroenterology. 2007 Dec;133(6):1882-92
references: 18054560
references: Genesis. 2004 Jul;39(3):186-93
references: 15282745
references: Differentiation. 2002 Dec;70(9-10):583-9
references: 12492499
references: Int J Cancer. 1996 Sep 27;68(1):14-20
references: 8895533
references: Am J Pathol. 1997 Jun;150(6):1977-84
references: 9176391
references: Carcinogenesis. 1997 Dec;18(12):2435-9
references: 9450492
references: Cell. 1996 Feb 9;84(3):345-57
references: 8608588
references: Growth Factors. 1991;5(1):57-68
references: 1772662
references: J Clin Invest. 2010 Jun;120(6):1824-35
references: 20484816
references: Exp Cell Res. 2009 Jan 1;315(1):39-49
references: 18950621
references: Cell Cycle. 2009 Aug 15;8(16):2549-56
references: 19597346
references: Dev Cell. 2005 Jun;8(6):843-54
references: 15935774
references: Oncogene. 2000 May 25;19(23):2774-9
references: 10851078
references: Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):13-9
references: 18093941
references: Cell. 2005 Dec 2;123(5):889-901
references: 16325582
references: Clin Colorectal Cancer. 2005 Jan;4(5):313-9
references: 15663834
references: Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9156-60
references: 1924379
references: J Clin Invest. 2008 Jul;118(7):2516-25
references: 18521188
references: J Cell Biol. 2003 Nov 10;163(3):535-45
references: 14610056
references: Trends Cell Biol. 2006 Sep;16(9):453-60
references: 16893648
references: Cancer Cell. 2007 Aug;12(2):145-59
references: 17692806
references: J Leukoc Biol. 2002 Jul;72(1):9-18
references: 12101257