Azoxymethane-induced rat aberrant crypt foci: Relevance in studying chemoprevention of colon cancer

Abstract

The pathogenesis of colon cancer involves sequential and multistep progression of epithelial cells initiated to a cancerous state with defined precancerous intermediaries. Aberrant crypt foci (ACF) represent the earliest identifiable intermediate precancerous lesions during colon carcinogenesis in both laboratory animals and humans. ACF are easily induced by colon-specific carcinogens in rodents and can be used to learn more about the process of colon carcinogenesis. For over two decades, since its first discovery, azoxymethane (AOM)-induced rodent ACF have served as surrogate biomarkers in the screening of various anticarcinogens and carcinogens. Several dietary constituents and phytochemicals have been tested for their colon cancer chemopreventive efficacy using the ACF system. There has been substantial effort in defining and refining ACF in terms of understanding their molecular make-up, and extensive research in this field is currently in progress. In chemoprevention studies, AOM-induced rat ACF have been very successful as biomarkers, and have provided several standardized analyses of data. There have been several studies that have reported that ACF data do not correlate to actual colon tumor outcome, however, and hence there has been an ambiguity about their role as biomarkers. The scope of this mini-review is to provide valuable insights and limitations of AOM-induced rat ACF as biomarkers in colon cancer chemoprevention studies. The role of the dynamics and biological heterogeneity of ACF is critical in understanding them as biomarkers in chemoprevention studies.

Haploinsufficiency ofSGO1results in deregulated centrosome dynamics, enhanced chromosomal instability and colon tumorigenesis

“…42,43 Previous reports indicated that, rather than simply being oncogenic, high chromosome instability from defects in mitotic machinery can be both oncogenic and tumor suppressive in an environment-dependent manner. 20,22,36 In our AOM-induced tumorigenesis assay, the SGO1 +/-mice showed a significant increase in size and frequency of ACF, which are precursor lesions of colonic tumors, [31][32][33][34][35] and an increased number of colonic tumors at the endpoint, indicating that the SGO1 defect can be an enhancing factor for colonic tumorigenesis. This observation is reminiscent of our previous results on colonic tumorigenesis with BubR1 haploinsufficiency mice, which show a spindle checkpoint defect and high mitotic chromosome instability.…”

“…4A). [31][32][33][34][35] Defects in chromosome cohesion are implicated in chromosome instability and colonic the mRNA expression, SGO1 protein level was also lower in SGO1 +/-cells than that in WT cells ( Fig. 1E and F).…”

Purple Rice Extract Supplemented Diet Reduces DMH-Induced Aberrant Crypt Foci in the Rat Colon by Inhibition of Bacterial β-Glucuronidase

“…In this protocol rats were treated with PRE mixed diet for 1 week before induction of ACF by DMH in order to study the modulating effect of xenobiotic metabolism in rat liver and the final outcome marker, ACF at 5 weeks of the experiment (Raju, 2008). Purple rice extract reduced the total number of ACF when compared to DMH-treated rats but the effects of the dosage were not significant.…”

Utility of models of the gastrointestinal tract for assessment of the digestion and absorption of engineered nanomaterials released from food matrices

“…Not only can these lesions modify barrier function, but high-dose chemotherapy regimens can also modify the digestive and absorptive function of the GI tract (Rubenstein et al, 2004). Several in vivo rodent models can be induced to develop premalignant lesions and tumors of the buccal cavity, esophagus, stomach, small intestine and colon that are similar to those observed in humans and are amenable to study interactions with dietary components (Chen & Lin, 2010;Garman et al, 2012;Lai et al, 2010;Raju, 2008;Raju & Bird, 2003;Tanaka, 2012;Zeineldin & Neufeld, 2013;Zhang & Moss, 2012). Such models could be useful for assessing not only the influence of cancer on NM uptake from the gut, but also beneficial targeting of ingested pharmaceutical or imaging NMs to gastrointestinal tumors.…”