Reference SummaryFischer JM, Oncogene 2012 Apr 19;31(16):2028-38

Title

Different phenotypic consequences of simultaneous versus stepwise Apc loss.

Authors

Fischer JM; Miller AJ; Shibata D; Liskay RM

Journal

Oncogene

Volume

31

Issue

16

Year

2012

Pages

2028-38

Abstract

APC is considered a gatekeeper for colorectal cancer (CRC). Cells with heterozygous APC mutations have altered expression profiles suggesting that the first APC hit may help set the stage for subsequent transformation. Therefore, we measured transformation efficiency following what we have designated as 'simultaneous' versus 'stepwise' Apc loss. We combined a conditional Apc allele (Apc(CKO)) with a Cre reporter gene and an out-of-frame Cre allele (Pms2(cre)) that stochastically becomes functional by a frameshift mutation in single cells. Loss of one Apc allele (Apc(CKO/+)) had little consequence, whereas simultaneous loss of both Apc alleles (Apc(CKO/CKO)) resulted in increased clonal expansion (crypt fission), consistent with the gatekeeper function of Apc. Interestingly, our analyses showed that most of the Apc-deficient crypts in Apc(CKO/CKO) mice appeared normal, with morphological transformation, including beta-catenin deregulation, occurring in only 17% of such crypts. To determine whether transformation efficiency was different following stepwise Apc loss, we combined Apc(CKO) with a germline mutant allele, either Apc(Min) or Apc(1638N). Transformation efficiency following stepwise Apc loss (Apc(Min/CKO) or Apc(1638N/CKO)) was increased five-fold and essentially all of the Apc-deficient cells were dysplastic. In summary, our data suggest that the gatekeeper function of Apc consists of two roles, clonal expansion and morphological transformation, because simultaneous Apc loss frequently leads to occult clonal expansion without morphological transformation, whereas stepwise Apc loss more often results in visible neoplasia. Finally, that Apc-deficient cells in certain scenarios can retain a normal phenotype is unexpected and may have clinical implications for surveillance strategies to prevent CRC.

Links

J:186141 – Mouse Genome Informatics
21892206 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

[not specified]-ApcMin/Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

[not specified]-Apctm1Rak/Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine - Small Intestine adenoma Intestine - Small Intestine

observed

[not specified]-Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine - Small Intestine adenoma - microadenoma Intestine - Small Intestine

observed

[not specified]-ApcMin/Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine - Small Intestine adenoma - microadenoma Intestine - Small Intestine

observed

[not specified]-Apctm1Rak/Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine - Small Intestine adenoma - microadenoma Intestine - Small Intestine

observed

[not specified]-Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine adenoma Intestine

0

[not specified]-Apctm2Rak/+ Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine adenoma Intestine

0

[not specified]-Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine adenoma Intestine

observed

[not specified]-ApcMin/+ Gt(ROSA)26Sortm1Sor Intestine adenoma Intestine

observed

[not specified]-Apctm1Rak/+ Gt(ROSA)26Sortm1Sor Intestine adenoma Intestine

observed

[not specified]-Apctm2Rak/+ Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine adenoma - microadenoma Intestine

0

[not specified]-Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine adenoma - microadenoma Intestine

observed

[not specified]-ApcMin/+ Gt(ROSA)26Sortm1Sor Intestine adenoma - microadenoma Intestine

observed

[not specified]-Apctm1Rak/+ Gt(ROSA)26Sortm1Sor Intestine adenoma - microadenoma Intestine

observed

[not specified]-Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine dysplasia Intestine

observed

[not specified]-Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine tumor Intestine

0

[not specified]-Apctm2Rak/+ Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine tumor Intestine

0

[not specified]-Apctm2Rak Gt(ROSA)26Sortm1Sor Pms2tm2(cre)Lisk Intestine tumor Intestine

observed