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Different phenotypic consequences of simultaneous versus stepwise Apc loss.

J M Fischer¹, A J Miller, D Shibata

¹Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.

|September 6, 2011

Summary

Adenomatous polyposis coli (APC) acts as a gatekeeper in colorectal cancer (CRC). Simultaneous APC loss causes clonal expansion, while stepwise loss leads to neoplasia, impacting CRC surveillance strategies.

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Area of Science:

Molecular biology
Cancer research
Genetics

Background:

Adenomatous polyposis coli (APC) is a key tumor suppressor gene.
APC mutations are crucial in colorectal cancer (CRC) development.
Altered expression in heterozygous APC mutations suggests a role in early transformation.

Purpose of the Study:

To investigate the transformation efficiency of simultaneous versus stepwise Apc loss.
To elucidate the dual role of APC in colorectal tumorigenesis.
To assess the implications for CRC surveillance.

Main Methods:

Utilized a conditional Apc allele (Apc(CKO)) combined with Cre reporter and frameshift-induced Cre alleles (Pms2(cre)) in mice.
Compared transformation efficiency in Apc(CKO/CKO) (simultaneous loss) versus Apc(Min/CKO) or Apc(1638N/CKO) (stepwise loss) models.
Analyzed crypt fission, morphological transformation, and β-catenin deregulation.

Main Results:

Simultaneous Apc loss (Apc(CKO/CKO)) led to increased clonal expansion (crypt fission) but only 17% morphological transformation.
Stepwise Apc loss (Apc(Min/CKO) or Apc(1638N/CKO)) increased transformation efficiency five-fold, with nearly all cells showing dysplasia.
Apc-deficient cells can retain a normal phenotype, suggesting occult expansion without overt transformation.

Conclusions:

APC's gatekeeper function involves both clonal expansion and morphological transformation.
Simultaneous Apc loss often results in occult clonal expansion without visible neoplasia.
Stepwise Apc loss more consistently leads to neoplastic transformation, with potential clinical implications for CRC surveillance.