Reference SummaryDavies EJ, J Pathol 2014 May;233(1):27-38

Title

PTEN loss and KRAS activation leads to the formation of serrated adenomas and metastatic carcinoma in the mouse intestine.

Authors

Davies EJ; Marsh Durban V; Meniel V; Williams GT; Clarke AR

Journal

J Pathol

Volume

233

Issue

1

Year

2014

Pages

27-38

Abstract

Mutation or loss of the genes PTEN and KRAS have been implicated in human colorectal cancer (CRC), and have been shown to co-occur despite both playing a role in the PI3' kinase (PI3'K) pathway. We investigated the role of these genes in intestinal tumour progression in vivo, using genetically engineered mouse models, with the aim of generating more representative models of human CRC. Intestinal-specific deletion of Pten and activation of an oncogenic allele of Kras was induced in wild-type (WT) mice and mice with a predisposition to adenoma development (Apc(fl/+) ). The animals were euthanized when they became symptomatic of a high tumour burden. Histopathological examination of the tissues was carried out, and immunohistochemistry used to characterize signalling pathway activation. Mutation of Pten and Kras resulted in a significant life-span reduction of mice predisposed to adenomas. Invasive adenocarcinoma was observed in these animals, with evidence of activation of the PI3'K pathway but no metastasis. However, mutation of Pten and Kras in WT animals not predisposed to adenomas led to perturbed homeostasis of the intestinal epithelium and the development of hyperplastic polyps, dysplastic sessile serrated adenomas and metastasizing adenocarcinomas with serrated features. These studies demonstrate synergism between Pten and Kras mutations in intestinal tumour progression, in an autochthonous and immunocompetent murine model, with potential application to preclinical drug testing. In particular, they show that Pten and Kras mutations alone predispose mice to the spectrum of serrated lesions that reflect the serrated pathway of CRC progression in humans. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.

Links

J:208067 – Mouse Genome Informatics
24293351 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Large Intestine - Colon tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

0

[not specified]-Apctm1Tno/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Large Intestine - Colon tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

0

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Tg(Vil1-cre/ERT2)23Syr Intestine - Large Intestine - Colon tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

0

[not specified]-Apctm1Tno/+ Tg(Vil1-cre/ERT2)23Syr Intestine - Large Intestine - Colon tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

0

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

33.33

[not specified]-Apctm1Tno/+ Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine adenoma - serrated
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

58.33

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine carcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

30.56

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine lesion
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine polyp - hyperplastic
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

22.22

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Apctm1Tno/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Apctm1Tno/+ Tg(Vil1-cre/ERT2)23Syr Intestine - Small Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Small Intestine

observed

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

0 - observed

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Tg(Vil1-cre/ERT2)23Syr Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Tg(Vil1-cre/ERT2)23Syr Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

0

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenocarcinoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

100

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Tg(Vil1-cre/ERT2)23Syr Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Tg(Vil1-cre/ERT2)23Syr Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenoma - microadenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine adenoma - microadenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Krastm1Bbd/+ Tg(Vil1-cre/ERT2)23Syr Intestine adenoma - microadenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno/+ Tg(Vil1-cre/ERT2)23Syr Intestine adenoma - microadenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Krastm1Bbd/+ Ptentm2Mak Tg(Vil1-cre/ERT2)23Syr Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

75

[not specified]-Krastm1Bbd/+ Tg(Vil1-cre/ERT2)23Syr Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

0