Effective chemoprevention strategies in APC driven mouse models of intestinal tumourigenesis


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Michael Hodder1,Patrizia Cammareri1,Dennis Timmerman1,Owen Sansom1

1CRUK Beatson Institute

Abstract

Background

Truncation of the negative regulator of the Wnt signalling pathway, Adenomatous Polyposis Coli (APC), represents one of the earliest commonly occurring events in Colorectal Cancer (CRC) progression. In addition, a number of factors substantially increase the risk of developing CRC, including inherited mutations in APC, such as Familial Adenomatous Polyposis (FAP). Here we exploit vulnerabilities in APC mutant stem cells and use chemo-preventative strategies to influence tumour initiation in the mouse intestinal epithelium.

Method

Using in vivo mouse models we mutate APC specifically in the Lgr5+ve stem cell population of the intestine. We subsequently challenge these models with short term therapeutic strategies to influence early lesions, and assess the ability of chemotherapy to influence mutant clone establishment, as well as tumour formation and overall survival.

Results

We demonstrate that APC deficient intestinal stem cells are more sensitive to chemotherapy when compared with wild type stem cells. In addition, we establish that short term therapeutic interventions, including those which cause DNA damage and those which specifically target apoptotic machinery, are able to influence tumour initiation, extend survival and reduce tumour numbers in mouse models. Furthermore, we identify that timing is crucial for therapeutic efficacy, as treatment of established tumours has no significant impact on tumour progression.

Conclusion

Overall we provide evidence that chemoprevention is a tenable approach to combat CRC, and could be of significant benefit to high risk patients, such as those with FAP. Similar to our mouse models, chemoprevention could offer more tangible patient benefit than treatment of established tumours. This work highlights that early lesions are exquisitely sensitive to a variety of therapies and that mutant clones can be eliminated and readily replaced with healthy stem cells prior to tumour formation.