Reference SummaryMutoh M, Cancer Res 2002 Jan 1;62(1):28-32

Title

 Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis.

Authors

 Mutoh M; Watanabe K; Kitamura T; Shoji Y; Takahashi M; Kawamori T; Tani K; Kobayashi M; Maruyama T; Kobayashi K; Ohuchida S; Sugimoto Y; Narumiya S; Sugimura T; Wakabayashi K

Journal

 Cancer Res

Volume

 62

Issue

 1

Year

 2002

Pages

 28-32

Abstract

 Accumulating evidence indicates that overproduction of prostanoids attributable to overexpression of cyclooxygenase-2 (COX-2) plays an important role in colon carcinogenesis. We have shown recently that the prostaglandin (PG) E receptor, EP(1), but not EP(3), is involved in mouse colon carcinogenesis. In line with our previous study, here we examined the role of prostanoid receptors in colon carcinogenesis using six additional lines of knockout mice deficient in prostanoid receptors EP(2), EP(4), DP, FP, IP, or TP. The animals were treated with the colon carcinogen, azoxymethane (AOM), and examined for the development of aberrant crypt foci (ACFs), putative preneoplastic lesions in the colon. Formation of ACFs was decreased only in the EP(4)-knockout mice, to 56% of the wild-type level. To confirm these results, we also examined the inhibitory effects of an EP(4)-selective antagonist, ONO-AE2-227, in the diet on the formation of AOM-induced colon ACFs in C57BL/6Cr mice and on the development of intestinal polyps in Min mice. ONO-AE2-227 at a dose of 400 ppm reduced the formation of ACFs to 67% of the control level, and intestinal polyp numbers in Min mice receiving 300 ppm were decreased to 69% of the control level. Plating efficiency assays showed that addition of 1.0 microM ONO-AE1-329, an EP(4)-selective agonist, resulted in a 1.8-fold increase in the colony number of the human colon cancer cell line, HCA-7, similar to the effect of PGE(2). Moreover, EP(4) mRNA expression was clearly observed in normal colon mucosa and colon tumors in mice. Our previous and present results indicate that PGE(2) contributes to colon carcinogenesis through its actions mediated through EP(1) and EP(4) receptors; therefore, antagonists for these two receptors may be good candidates as chemopreventive agents against colon cancer.

Links

 J:73944 – MGI References
11782353 – National Library of Medicine/PubMed

Strain Notes

Strain Note
B6;129P2 Littermate controls for Ptger4tm1Aic knockouts.
Mice were generated by mating chimeric mice with C57BL/6Cr males purchased from Japan SLC, Inc. Homozygous mutants were obtained by interbreeding offspring.
B6.129P2 Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
Littermate controls for Ptgirtm1Sna knockouts.
B6.129P2 Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
Littermate controls for Ptgfrtm1Aic knockouts.
B6.129P2 Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
Littermate controls for Ptgdrtm1Sna knockouts.
B6.129P2 Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
Littermate controls for Ptger2tm1Sna knockouts.
B6.129P2-Ptgdrtm1Sna Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
B6.129P2-Ptger2tm1Sna Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
B6;129P2-Ptger4tm1Sna Mice were generated by mating chimeric mice with C57BL/6Cr males purchased from Japan SLC, Inc. Homozygous mutants were obtained by interbreeding offspring.
B6.129P2-Ptgfrtm1Sna Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
B6.129P2-Ptgirtm1Sna Authors did not provide the number of generations they backcrossed mice onto C57BL/6Cr, using males purchased from Japan SLC, Inc.
C57BL/6J-ApcMin/+ Mice were obtained from The Jackson Laboratory at 6 weeks old.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6JJcl Intestine - Large Intestine - Colon adenocarcinoma - well-differentiated
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2-Ptger2tm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2 Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6;129P2-Ptger4tm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6;129P2 Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2-Ptgdrtm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2 Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2-Ptgfrtm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2 Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2-Ptgirtm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.129P2 Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6;129P2 Intestine - Large Intestine - Colon foci - aberrant crypt (ACF) Intestine - Large Intestine - Colon

0
B6;129P2-Ptger4tm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF) Intestine - Large Intestine - Colon

0
C57BL/6CrSlc Intestine - Large Intestine - Colon foci - aberrant crypt (ACF) Intestine - Large Intestine - Colon

0
C57BL/6CrSlc Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
 Intestine - Large Intestine - Colon

0
C57BL/6CrSlc Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
C57BL/6CrSlc Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.Cg-Tbxa2rtm1Sna Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
B6.Cg Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • azoxymethane (AOM)
 Intestine - Large Intestine - Colon

observed
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon polyp Intestine - Large Intestine - Colon

observed
C57BL/6J-ApcMin/+ Intestine - Large Intestine - Colon polyp
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
 Intestine - Large Intestine - Colon

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal polyp Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Distal polyp
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
 Intestine - Small Intestine - Distal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial polyp Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Medial polyp
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
 Intestine - Small Intestine - Medial

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal polyp Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine - Small Intestine - Proximal polyp
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
 Intestine - Small Intestine - Proximal

observed
C57BL/6J-ApcMin/+ Intestine polyp Intestine

observed
C57BL/6J-ApcMin/+ Intestine polyp
  • 2-[2-{2-(1-naphthyl)propanoylamino}phenyl]methylbenzoic acid (ONO-AE2-227)
 Intestine

observed