Characterisation of aberrant crypt foci in carcinogen-treated rats: association with intestinal carcinogenesis

Caderni, Giovanna; Giannini, A. James; Lancioni, L.; Luceri, Cristina; Biggeri, Annibale; Dolara, Piero

doi:10.1038/bjc.1995.148

Cited by 73 publications

(53 citation statements)

References 13 publications

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“…37 The localization of b-catenin was also determined in ACF isolated in HID-AB-stained colon. Our previous work 7,31 and data presented here indicate that ACF identified in HID-AB colon and ACF as seen in MB-stained colon are strongly correlated. We found that ACF isolated in HID-AB, though to a lesser extent than MDF, have altered expression of b-catenin, in agreement with data on human ACF, 11 although some authors did not find alteration in b-catenin localization in rodent ACF.…”

Section: Discussionsupporting

confidence: 67%

“…The method is similar to the HID-AB staining procedure that we 7,8 and others 9 use to identify MDF; this method only omits the preliminary staining of the colon with an high-iron diamine (HID) solution, a step that makes it possible to distinguish between sialomucin and sulfomucins production. 31 Although it is possible that Yoshimi's method will give satisfying results in the future, we think that more validation experiments should be performed before adopting it to identify MDF. In fact, a considerable fraction (about 24%) of the lesions identified as MDF by these authors turned out to be normal-like crypts at the histology.…”

Section: Discussionmentioning

confidence: 98%

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Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Femia

Bendinelli

Giannini

et al. 2005

Intl Journal of Cancer

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Mucin-depleted foci (MDF) are purported preneoplastic lesions that can be easily visualized in the unsectioned colon of carcinogen-treated rats stained with high-iron diamine alcian blue (HID-AB). In F344 rats treated twice with 150 mg/kg of 1,2-dimethylhydrazine (DMH) and sacrificed after 5, 9, 13 and 28 weeks, MDF increased over time from 5 to 13 weeks, whereas they decreased at 28 weeks, when tumors appear. MDF multiplicity (crypts/MDF) linearly increased with time. Increasing doses of DMH (100, 150 and 200 mg/kg 3 2 times) caused a dose-related increase in MDF. Mutations in Ctnnb1 gene codifying for b-catenin were identified with PCR amplification and direct sequencing in 6/15 tumors (40%), 7/28 MDF (25%) and 2/27 (7%) aberrant crypt foci (ACF) identified in HID-AB-stained colon. All mutations in tumors and MDF caused amino acid substitution, while one mutation in ACF was silent. b-catenin detected at membrane level by immunohistochemistry was markedly reduced in MDF and tumors and, to a lesser extent, in ACF identified with HID-AB. By contrast, nuclear localization of b-catenin was significantly increased in MDF and tumors, while no variation was observed in ACF. b-catenin cytoplasmic expression was also significantly increased in MDF and tumors but to a lesser extent in ACF. In conclusion, MDF are induced dose-dependently by DMH, increase in size with time, have mutations in the b-catenin gene and marked alterations in b-catenin cellular localization. Since all these phenomena are considered specific steps for colon tumorigenesis, these results further support the hypothesis that MDF are cancer precursors and can be proposed as endpoints in short-term carcinogenesis experiments. ' 2005 Wiley-Liss, Inc.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 98%

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Femia

Bendinelli

Giannini

et al. 2005

Intl Journal of Cancer

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“…However, the ACF studied had variable dimensions and included a certain number of lesions of larger size (11 ACF with 15 or more AC). We previously demonstrated (Caderni et al, 1995) that mild dysplastic characters (such as nuclear atypia, secretion of sialomucins and luminal alterations) are progressively increased during ACF growth. Similarly, Otori et al (1995) found a correlation between crypt multiplicity and dysplasia, although they also found large ACF with no signs of dysplasia.…”

Section: Discussionmentioning

confidence: 99%

“…The histological classification of ACF in both humans and experimental animals is a matter of debate (Bird et al, 1989;Bird and Pretlow, 1992;Caderni et al, 1995;Otori et al, 1995). In our study we did not evaluate the level of dysplasia in the ACF tested.…”

Section: Discussionmentioning

confidence: 99%

Mutations of the Apc gene in experimental colorectal carcinogenesis induced by azoxymethane in F344 rats

Filippo

Caderni²,

Bazzicalupo³

et al. 1998

Br J Cancer

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Summary We investigated in the rat the role of the Apc gene, which is mutated in familial adenomatous polyposis and sporadic colon cancer in the process leading from normal colonic mucosa to aberrant crypt foci (ACF) and finally to adenomas and adenocarcinomas. We analysed mutations in exon 15 of the rat Apc gene using in vitro synthesized protein assay in 66 ACF and in 28 colon tumours induced by azoxymethane. No Apc mutations were found in ACF, whereas five mutations were found in the tumours. The data suggest that mutations of the Apc gene are associated with the transition from ACF to adenoma and adenocarcinoma and not from normal mucosa to ACF.Keywords: Apc gene; aberrant crypt foci; colon cancer; experimental carcinogenesis; azoxymethane According to current views, colon carcinogenesis is a multistep process in which preneoplastic lesions accumulate in mucosa cells, finally leading to neoplastic transformation (Kinzler and Vogelstein, 1996). Many molecular events have been suggested to play a role in the transition from normal colon mucosa to cancer, such as the activation of oncogenes, the inactivation or loss of tumour-suppressor genes and mutations in DNA repair genes (Kinzler and Vogelstein, 1996). According to a commonly accepted model of colorectal tumorigenesis, K-ras and APC (adenomatous polyposis coli) gene mutations are early genetic events (Kinzler and Vogelstein, 1996). The APC gene in mutated in familial adenomatous polyposis (FAP) and in human sporadic colon tumours with a frequency ranging from 40% to 80% (Nakamura, 1993;De Benedetti et al, 1994;Kinzler and Vogelstein, 1996). The human APC gene (exons 1-15) contains an open reading frame of over 8500 nucleotides (Groden et al, 1991;Kinzler et al, 1991) and encodes for a cytoplasmic protein of 300 kDa that binds to 3-catenin (Rubinfeld et al, 1996), suggesting that APC product might regulate cell adhesion. About 50-60% of the somatic mutations of the APC gene are clustered in a 700-bp region, designated in humans as the mutation cluster region (MCR) (Nakamura, 1993). More than 95% of the mutations in the human APC gene are nonsense or frameshift mutations that result in truncated proteins (Nakamura, 1993;Powell et al, 1993).Aberrant crypt foci (ACF) have been suggested to be the first preneoplastic lesions preceding the development of adenomas and carcinomas (Bird, 1987). ACF are easily induced in experimental animals by a variety of carcinogens (Bird, 1987;Bruce et al, 1993) and have been described in humans with sporadic colon cancer and with familial adenomatous polyposis coli (Pretlow et al, 1991;Roncucci et al, 1991). ACF have been widely used as end points in experimental colon carcinogenesis , although some authors have not observed a correlation between ACF formation and colon cancer (Hardmann et al, 1991 Correspondence to: G Caderni Azoxymethane (AOM), one of the most extensively studied colon carcinogens, is able to induce both ACF and tumours in rats, and AOM-induced colon carcinogenesis is a widely used model for studying the mult...

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“…When PLU and PEG were directly compared, the number of ACF was smaller in PLU-fed than in PEG-fed rodents (Tables 2 and 3), but the difference was significant in mice only. In addition, PLU was more potent than PEG to decrease the number of large ACF, a better carcinogenesis endpoint than total ACF (Caderni et al, 1995). To summarize our previous rat studies, a 30-day PEG treatment decreases the ACF number 6-fold (median of 6 independent studies) Parnaud et al, 1999;Corpet et al, 2000).…”

Section: Discussionmentioning

confidence: 80%

Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice

et al. 2001

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Polyethylene-glycol (PEG) is a strong inhibitor of colon cancer in rats, and the most potent suppressor of aberrant crypt foci. 9 PEG-like block copolymers were tested in rodents, after an azoxymethane injection. Dietary pluronic F68 led to a 98.6% reduction in the number of aberrant crypt foci in a first rat study ( P < 0.0001). Next 3 studies confirmed this pluronic efficacy in rats and mice. This non-toxic laxative seems roughly 5 times more potent than PEG for chemoprevention. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Characterisation of aberrant crypt foci in carcinogen-treated rats: association with intestinal carcinogenesis

Cited by 73 publications

References 13 publications

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Mucin‐depleted foci have β‐catenin gene mutations, altered expression of its protein, and are dose‐ and time‐dependent in the colon of 1,2‐dimethylhydrazine‐treated rats

Mutations of the Apc gene in experimental colorectal carcinogenesis induced by azoxymethane in F344 rats

Pluronic F68 block polymer, a very potent suppressor of carcinogenesis in the colon of rats and mice

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