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 – Mouse Genome Informatics
14514656 – National Library of Medicine/PubMed

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