Investigation of the Role of Alcohol in Colorectal Tumour Development in Mouse Models


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Mike Mueller1,Ying Zhou1,Mark J Arends1
1Edinburgh Cancer Research Centre

Abstract

Background

Alcohol has been classified as carcinogenic for different organs, including the colorectum (IARC 2007). Underlying mechanisms are likely to involve genotoxic effects of the ethanol metabolite acetaldehyde, but have not been elucidated yet for the colorectum. The aldehyde dehydrogenase Aldh1b1 has a high affinity for acetaldehyde, second only to Aldh2, and is highly expressed in the intestine. This study aims to analyse the effects of long term alcohol consumption on colorectal carcinogenesis in wild type (wt) and Aldh1b1 knockout (KO) mice.

Method

20% (v/v) ethanol was administered to wt and Aldh1b1-KO mice via drinking water for one year while control groups received water (n=14-15). All abdominal organs were examined for tumours during necropsy. Intestines were analysed as whole mounts and all tumours were verified by histopathology. Acetaldehyde levels in plasma were determined using an enzyme-based assay.

Results

No tumours were detected in water-treated littermates, whereas ethanol-treated mice developed intestinal tumours (4/14 (29%) of wt and 4/15 (27%) of Aldh1b1-KO mice, 8 and 11 tumours per group). While the effect of ethanol on tumour development was significant, there was no influence of the genotype on tumour incidence, number or size. However, only some tumours of the ethanol-treated Aldh1b1-KO group showed evidence of early invasive adenocarcinoma. Enhanced plasma acetaldehyde levels were found in ethanol-treated Aldh1b1-KO mice.

Conclusion

Evidence for an involvement of ethanol in colorectal carcinogenesis so far comes from epidemiological data as well as from mouse models with oncogene activation or carcinogen administration. This is the first study showing that long term ethanol consumption leads to intestinal cancer development in wt and Aldh1b1-KO mice. Effects of Aldh1b1 loss could not be substantiated in terms of tumour incidence, number or size. However there were indications of an enhanced progression to malignancy in Aldh1b1-KO mice that could possibly be linked with increased acetaldehyde levels.