Studies on Promotion of Colonic ACF in rats,
not yet linked to Medline (e.g., abstracts from congress)

• W. Robert Bruce
  (The Ontario Cancer Institute & University of Toronto)
  Effect of hemoglobin, cooked or not, on aberrant crypt promotion in the colon of azoxymethane-induced rats
  Unpublished data. Personnal communication to Denis E. Corpet, 1993
  
  
• Femia Angelo Pietro, Maddalena Salvadori, Piero Dolara, Consuelo Bottini, Luciana Tessitore, Giovanna Caderni
  Proc Amer Assoc Cancer Res 2005; 46: [Abstract #3931]. AACR 96th Annual Meeting
  Characterization of mucin-depleted foci (MDF) as biomarkers of colon carcinogenesis in 1,2-dimethylhydrazine(DMH)-induced rats treated with polyethylene-glycol (PEG).
  Mucin-depleted foci (MDF) characterized by absent or scant mucous production were recently described by our group in the colon of carcinogen-treated rats (1). MDF can be easily identified along the entire mucosal surface of unembedded colon and are histologically dysplastic; moreover, MDF increase in rats treated with known promoters of colon carcinogenesis while decrease with chemopreventive agents such as piroxicam. On this basis, we suggested that MDF represent preneoplastic lesions that could be used as biomarkers for carcinogenesis. To further confirm this hypothesis, we studied MDF in 1,2-dimethylhydrazine (DMH)-initiated rats treated with polyethylene glycol (PEG) which has been demonstrated to inhibit colon cancer and preneoplastic lesions in carcinogen-treated rats (2). F344 male rats were treated weekly with DMH (150 mg/kg x 2, s.c) and then randomized into: control group, given AIN76 diet and water ad libitum and PEG group, fed AIN-76 diet and drinking water supplemented with 5% PEG. Sixteen weeks after the first dose of DMH, the total number of MDF was drastically reduced (P<0.01) in rats treated with PEG (MDF/ colon were 5.2±0.8 in controls and 0.1 ±0.1 in PEG-treated rats, means ±SE). Since PEG reduces colon cancer, MDF are correlated with carcinogenesis and can be proposed as endpoints to study the modulation of colon carcinogenesis in short-term experiments. To further characterize these lesions we studied the expression of p27, an inhibitor of cyclin-dependent kinases, which inhibits progression of the cell cycle (3). Immunohystochemical identification of p27 was determined in paraffin sections of MDF (15 samples) and in their paired normal mucosa (NM), all challenged with p27 antibody (monoclonal mouse anti-human p27Kip1). Compared with NM, the nuclear expression of p27 was markedly reduced in MDF (P<0.001) (cells with nuclear localization of p27 as % of total cells scored were 9.7%±1.4, and 25.4±1.7 % in MDF and NM, respectively, means ±SE). Cytoplasmic expression of p27 was not varied in MDF. In conclusion, MDF are correlated with colon carcinogenesis and have a marked reduction of nuclear p27, since such alteration has been reported in many human tumours including colon cancer, these results confirm the precancerous nature of MDF. 1) Caderni et al., Cancer Res 2003; 63: 2388-92. 2) Parnaud et al., Cancer Res 1999; 59: 5143-47. 3) Weinstein, Carcinogenesis 2000, 21: 857-864.
  
  
• Flynn C., Masako Nakanishi, David Montrose, Michael Johnson, Daniel W. Rosenberg.
  Promotional effect of deoxycholic acid in murine model resistant to colorectal cancer
  Proc Amer Assoc Cancer Res 2005;46:[Abstract #1198].
  AKR/J mice are resistant to the tumorigenic properties of the colon carcinogen, azoxymethane (AOM). Upon AOM exposure, only limited numbers of preneoplastic lesions, referred to as aberrant crypt foci (ACF), are formed in the colon, and tumor progression is a rare event. To determine whether inherent tumor resistance can be overcome by concomitant exposure to a dietary tumor promoter, AOM-exposed AKR/J mice were fed a diet containing 0.25% deoxycholic acid (DCA). DCA exposure was begun one week prior to or one week after initiation with AOM. Mice started on the DCA diet prior to AOM developed a higher number of ACF (2-fold) compared to AOM exposed non-DCA fed mice (15.5 ± 0.96 vs. 6.17 ± 0.48 respectively). However, when DCA exposure was started after AOM treatment (post-initiation), ACF formation was further enhanced (up to 4-fold) and colonic lesions were characterized by a higher degree of dysplasia (34.00 ± 1.22). The increase in ACF number was correlated with the presence of nuclear b-catenin, assessed by immunohistochemical staining. In fact, 77% of ACF in the colons of mice fed DCA after AOM had positive b-catenin nuclear staining. In contrast, only 33% of ACF from mice exposed to DCA prior to AOM treatment contained positive staining nuclei. These results indicate that exposure to DCA, an important digestive component, is sufficient to sensitize a resistant colonic epithelium to formation of high-grade dysplasia, and further suggest that b-catenin nuclear translocation may play a key role in DCA-mediated colonic dysplasia.
  
  

Clik here to go back to main page & database

---

Corpet DE & Taché S, 2002, Nutrition & Cancer - & - DE Corpet & F Pierre, 2003, Cancer Epidemiol. Biomarkers Prevention
colorectal cancer chemoprevention database & Mirror site