Original ResearchBasic and Translational—Alimentary TractMutant Kras Promotes Hyperplasia and Alters Differentiation in the Colon Epithelium but Does Not Expand the Presumptive Stem Cell Pool
Section snippets
Mice
KrasLSL-G12D/+ mice have been described previously.15 We crossed KrasLSL-G12D/+ mice to CDX2P9.5-G22Cre (G22Cre) transgenic mice to activate the mutant Kras allele in the intestinal tract.14 To monitor Cre expression, G22Cre mice or G22Cre KrasLSL-G12D/+ mice were intercrossed with mice carrying the Gt(ROSA)26Sortm1(EYFP)Cos/J reporter allele (Jackson Laboratory, Bar Harbor, ME). To target Apc alleles, G22Cre mice or CDX2P 9.5-NLS Cre mice were intercrossed with mice homozygous for Apc targeted
Activation of KrasG12D Mutant Allele in Mouse Colon Epithelium Promotes HPP-like Features
We used the CDX2P-G22Cre transgenic mouse line (referred to as G22Cre),14 which expresses Cre in epithelial cells in terminal ileum, cecum, colon, and rectum, to activate a latent oncogenic KrasLSL-G12D allele.15 Cre-mediated recombination removes transcriptional stop elements, resulting in expression of the mutant KrasLSL-G12D allele under control of its endogenous regulatory elements. Using mice carrying a gene for enhanced yellow fluorescence protein (EYFP) at the Gt(ROSA)26Sor locus19 to
Discussion
Roughly 40% of human CRCs and larger adenomas carry KRAS-activating mutations.5, 35 Mutant KRAS alleles are functionally significant in advanced CRC cells.8 In light of these data on KRAS mutations in CRC pathogenesis, it has not previously been clear why human HPPs with somatic KRAS (or BRAF) mutations have nominal risk of progressing to CRC.2 One well-documented difference between colon adenomas, which are precursor lesions for CRC, and HPPs is that most adenomas have APC inactivation and
Acknowledgments
G.T.B.'s current affiliation is: De Duve Institute, BCHM/GRM, Universite Catholique de Louvain, Belgium.
The authors thank Dr Hideyuki Okano for generously providing the Msi1 antibody and Dr Joel Greenson for providing human colon tissue, Dr Shuling Fan for help with immunofluorescence microscopy, Cameron Bothner for graphics assistance, and Brandon Fishman for comments on the paper.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grant CA082223 and Department of Defense award W81XWH-09-2-0014.