Reference SummaryMollersen L, Carcinogenesis 2004 Jan;25(1):149-53

Title

 Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (Min)/+ mice.

Authors

 Mollersen L; Paulsen JE; Olstorn HB; Knutsen HK; Alexander J

Journal

 Carcinogenesis

Volume

 25

Issue

 1

Year

 2004

Pages

 149-53

Abstract

 Chemopreventive activity by retinoic acid (RA) has been demonstrated previously in rat colon. The spontaneous tumourigenesis in the Min/+ mouse, which harbours a germline mutation in the tumour suppressor gene adenomatous polyposis coli (Apc), is characterized by inactivation of Apc, nuclear accumulation of beta-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/beta-catenin signalling. Recently it was reported that beta-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing beta-catenin/TCF regulated transcription. Our hypothesis was therefore that dietary supplementation with all-trans RA may inhibit the Apc-driven tumourigenesis in Min/+ mice. Surprisingly, in two different experiments the results showed that dietary RA significantly stimulated both the formation and growth of small intestinal tumours. In the first experiment Min/+ mice were exposed to 50 mg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine/kg bodyweight at day 3-6 after birth and then treated with 50 mg/kg dietary RA in 1-3 weeks from the age of 2 weeks. In the second experiment the mice were not treated with carcinogen, and the diet was supplemented with 5 or 10 mg/kg RA from the age of 4 weeks until termination of the experiment at 11 weeks. Immunohistochemical studies revealed no differences in beta-catenin, cyclin D1 or proliferating cell nuclear antigen staining following RA treatment. There was no intestinal toxicity in mice fed 10 mg/kg RA, indicating that the increased tumourigenesis in Min/+ mice is a specific effect of all-trans RA.

Links

 J:87705 – MGI References
14514656 – National Library of Medicine/PubMed

Strain Notes

Strain Note
C57BL/6J Mice were bred at the Norwegian Institute of Public Health, Oslo, Norway.
C57BL/6J-ApcMin/+ Mean body weights were 26.0 +/0 1.5, 24.0 +/- 1.1, and 23.0 +/- 1.0 g for vehicle, 5 and 10mg/kg dietary RA, respectively.
Mean final body weights were 23.5 +/- 0.9 and 23.2 +/- 1.1 g for PhIP treated mice and PhIP treated mice fed short-term 50mg/kg dietary RA, respectively.
Mice were bred at the Norwegian Institute of Public Health, Oslo, Norway from mice originally purchased from The Jackson Laboratory. Males carrying ApcMin were mated to wildtype C57BL/6 females originating from Bomholt, Denmark.
% PCNA staining cells in normal tissue of distal small intestine: 46.7 +/- 1.5% were weakly staining, 26.6 +/- 1.4% were strongly stained.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon tumor
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
  • retinoic acid (RA)
 Intestine - Large Intestine - Colon

58
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon tumor Intestine - Large Intestine - Colon

30
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon tumor
  • retinoic acid (RA)
 Intestine - Large Intestine - Colon

53 - 80
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon tumor
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
 Intestine - Large Intestine - Colon

57
C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
 Intestine - Small Intestine

100
C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor
  • 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
  • retinoic acid (RA)
 Intestine - Small Intestine

100
C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor Intestine - Small Intestine

100
C57BL/6J-ApcMin/+ Intestine - Small Intestine tumor
  • retinoic acid (RA)
 Intestine - Small Intestine

100
C57BL/6J Intestine tumor
  • retinoic acid (RA)
 Intestine

0