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

Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, C218 Banting Building, Postal Locator 2202D, Ottawa, K1A 0L2, Ontario, Canada.
World Journal of Gastroenterology (Impact Factor: 2.37). 12/2008; 14(43):6632-5. DOI: 10.3748/wjg.14.6632
Source: PubMed

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.

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    • "Although ACF incidence is related to colon carcinogenesis, these preneoplastic lesions are heterogeneous and have different molecular characteristics (Raju, 2008). Thus, ACF with 1, 2 or 3 crypts per focus may regress over time, and those with greater multiplicity (ACF ≥ 4 crypts) may progress to form colon neoplasia and are therefore considered more aggressive (Magnuson et al., 1993; Perše and Cerar, 2011; Raju, 2008). In the present study, TB treatment reduced the ACF ≥ 4 crypts, suggesting that TB acts on more aggressive, aberrant crypt foci and reinforcing its role as an important chemopreventive agent in colon carcinogenesis. "
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    ABSTRACT: The chemopreventive activity of the histone deacetylase inhibitor (HDACi) tributyrin (TB), a prodrug of butyric acid (BA), was evaluated in a rat model of colon carcinogenesis. The animals were treated with TB (TB group: 200 mg/100 g of body weight, b.w.) or maltodextrin (MD isocaloric control group: 300 mg/100 g b.w.) daily for 9 consecutive weeks. In the 3rd and 4th weeks of treatment, the rats in the TB and MD groups were given DMH (40 mg/kg b.w.) twice a week. After 9 weeks, the animals were euthanized, and the distal colon was examined. Compared with the control group (MD group), TB treatment reduced the total number of aberrant crypt foci (ACF; p < 0.05) as well as the ACF with ≥ 4 crypts (p < 0.05), which are considered more aggressive, but not inhibited the formation of DMH-induced O6-methyldeoxyguanosine DNA adducts. The TB group also showed a higher apoptotic index (p < 0.05) and reduced DNA damage (p < 0.05) compared with MD group. TB acted as a HDACi, as rats treated with the prodrug of BA had higher levels of histone H3K9 acetylation compared with the MD group (p < 0.05). TB administration resulted in increased colonic tissue concentrations of BA (p < 0.05) compared with the control animals. These results suggest that TB can be considered a promising chemopreventive agent for colon carcinogenesis because it reduced the number of ACF, including those more aggressive. Induction of apoptosis and reduction of DNA damage are cellular mechanisms that appear to be involved in the chemopreventive activity of TB.
    Toxicology and Applied Pharmacology 04/2014; 276(2). DOI:10.1016/j.taap.2014.02.004 · 3.71 Impact Factor
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    • "AOM-induced rats develop colon tumors similar to those found in the human colon. This animal model is ideal to study colon tumorigenesis with an opportunity to intervene with chemicals, drugs or nutrients in a medium-term time frame (24-30 weeks post AOM-treatment), thus targeting a chronic and sustainable exposure [28,29]. Colon tumor data derived from studies using the AOM rat model have been successful in assessing preclinical efficacy relating to human relevance [29]. "
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    ABSTRACT: Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet) reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control) or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM) or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu) mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control) or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a "complete carcinogen", but acts as a "co-carcinogen" by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters.
    PLoS ONE 09/2013; 8(9):e73916. DOI:10.1371/journal.pone.0073916 · 3.23 Impact Factor
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    • "ACF are described as lesions comprising enlarged crypts that are slightly elevated above the surrounding mucosa and whose crypts stain densely with methylene blue. ACF often have a slit-shaped luminal opening and an increased pericryptal space.2-4 In experimental animal models, colon carcinogens can induce various kinds of growth patterns, topographic features and numbers of ACF depending on the experimental protocol. "
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    ABSTRACT: The purpose of this study was to investigate the malignant potential of aberrant crypt foci (ACF) by measuring the multiplicity of crypts and lectin expression in the early and late stages of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis. Six-week-old Wistar rats were injected subcutaneously with DMH for 27 weeks. We classified ACF according to the number of crypts per ACF as a few crypts (≤3 crypts, FC ACF) or numerous crypts (≥4 crypts, NC ACF). Immunohistochemistry was used to evaluate lectin expression. In the early stage, FC ACF (590/1,902, 31.0%) occurred more frequently than NC ACF (35/449, 7.8%); whereas in the late stage, NC ACF (176/449, 39.2%) occurred more frequently than FC ACF (324/1,902, 17.0%). The number of ACF peaked at 15 to 20 weeks. The ratio of NC/FC ACF increased gradually during carcinogenesis. The expression of both UEA1 and PNA was higher in NC ACF than FC ACF. Lectin expression increased in the late stage compared with the early stage. The expression of lectin was higher in NC ACF and ACF in the late stage. Therefore, ACF with higher multiplicities in the late stage may have more malignant potential in DMH-induced colon carcinogenesis.
    Gut and liver 04/2012; 6(2):229-34. DOI:10.5009/gnl.2012.6.2.229 · 1.81 Impact Factor
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