Mucin Depleted Foci (MDF) Have B-catenin Gene Mutations, Altered Expression of its Protein and Are Dose- and Time–Dependent in the Colon of 1,2-Dimethylhydrazine (DMH)–Treated Rats.

Department of Pharmacology, University of Florence, Firenze, Italy.
International Journal of Cancer (Impact Factor: 5.01). 08/2005; 116(1):9-15. DOI: 10.1002/ijc.20981
Source: PubMed

ABSTRACT 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 x 2 times) caused a dose-related increase in MDF. Mutations in Ctnnb1 gene codifying for beta-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. Beta-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 beta-catenin was significantly increased in MDF and tumors, while no variation was observed in ACF. Beta-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 beta-catenin gene and marked alterations in beta-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.

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Available from: Benedetta Bendinelli, Nov 13, 2014
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    • "These lesions are identified as uncoloured patches on unsectioned colon coloured with HID Alcian blue (Femia et al., 2004). However, it is likely that MDF and BCAC are very similar lesions (Femia et al., 2005). We showed previously (Bara et al., 2003; Maurin et al., 2007) that the M1/MUC5AC gastric mucin is expressed at the very beginning of mucosa modification during the course of carcinogenesis induced by intrarectal instillations of Nmethyl-N -nitro-N-nitrosoguanidine (MNNG). "
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    • "Both pathways lead to altered morphology, which can be identified as dysplasia at the microscopic level. In addition various signs may be seen at the macroscopic level, which include ACF and mucin depleted foci (MDF) (Femia et al., 2005). Some, but not all, of these lesions progress to become adenomas, which may eventually invade the muscularis mucosa and become adenocarcinomas. "
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