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A hypermorphic epithelial β-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations.

Buchert M, Rohde F, Eissmann M, Tebbutt N, Williams B, Tan CW, Owen A, Hirokawa Y, Gnann A, Orend G, Orner G, Dashwood RH, Heath JK, Ernst M, Janssen KP - Dis Model Mech (2015)

Bottom Line: Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers.We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33(ΔN-Bcat) mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis.Collectively, our data indicate that epithelial expression of ΔN(1-131)-β-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/β-catenin pathway to facilitate and promote tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia michael.buchert@onjcri.org.au klaus-peter.janssen@lrz.tum.de.

No MeSH data available.


Related in: MedlinePlus

The intestinal epithelium of Bcat mice has increased susceptibility to mutagen-induced carcinogenesis. (A) Representative methylene blue-stained large intestine of Wt and Bcat mice 5 weeks after the last of six consecutive azoxymethane (AOM) injections (scale bar=400 µm). (B) Enumeration of aberrant crypt foci in the colonic epithelium of Wt and Bcat mice (mean±s.d., n=15 mice, *P<0.05). (C) Photomicrographs of longitudinally opened and pinned out colons from Wt and Bcat mice 16 weeks after last injection of AOM (scale bar=1 cm). (D) Hematoxylin and eosin stain of a representative colonic adenoma excised from a Bcat mouse 16 weeks after the last AOM injection (scale bar=20 µm). (E) Enumeration of macroscopically visible adenomas in AOM-challenged Wt and Bcat mice (mean±s.d., n=10-11 mice, *P<0.05).
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DMM019844F4: The intestinal epithelium of Bcat mice has increased susceptibility to mutagen-induced carcinogenesis. (A) Representative methylene blue-stained large intestine of Wt and Bcat mice 5 weeks after the last of six consecutive azoxymethane (AOM) injections (scale bar=400 µm). (B) Enumeration of aberrant crypt foci in the colonic epithelium of Wt and Bcat mice (mean±s.d., n=15 mice, *P<0.05). (C) Photomicrographs of longitudinally opened and pinned out colons from Wt and Bcat mice 16 weeks after last injection of AOM (scale bar=1 cm). (D) Hematoxylin and eosin stain of a representative colonic adenoma excised from a Bcat mouse 16 weeks after the last AOM injection (scale bar=20 µm). (E) Enumeration of macroscopically visible adenomas in AOM-challenged Wt and Bcat mice (mean±s.d., n=10-11 mice, *P<0.05).

Mentions: To establish whether expression of the ΔN-Bcat transgene sensitized mice to chemical tumorigenesis, we challenged Bcat mice with the organotropic carcinogen azoxymethane (AOM). Mice were then analysed 5 and 12 weeks after the last of six consecutive AOM injections, and colons were stained in methylene blue to identify aberrant crypt foci (McLellan and Bird, 1988). Compared with Wt mice, Bcat mice harbored more aberrant crypt foci and more adenomatous polyps (Fig. 4A-C,E); however, these consistently remained well differentiated (Fig. 4D).Fig. 4.


A hypermorphic epithelial β-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations.

Buchert M, Rohde F, Eissmann M, Tebbutt N, Williams B, Tan CW, Owen A, Hirokawa Y, Gnann A, Orend G, Orner G, Dashwood RH, Heath JK, Ernst M, Janssen KP - Dis Model Mech (2015)

The intestinal epithelium of Bcat mice has increased susceptibility to mutagen-induced carcinogenesis. (A) Representative methylene blue-stained large intestine of Wt and Bcat mice 5 weeks after the last of six consecutive azoxymethane (AOM) injections (scale bar=400 µm). (B) Enumeration of aberrant crypt foci in the colonic epithelium of Wt and Bcat mice (mean±s.d., n=15 mice, *P<0.05). (C) Photomicrographs of longitudinally opened and pinned out colons from Wt and Bcat mice 16 weeks after last injection of AOM (scale bar=1 cm). (D) Hematoxylin and eosin stain of a representative colonic adenoma excised from a Bcat mouse 16 weeks after the last AOM injection (scale bar=20 µm). (E) Enumeration of macroscopically visible adenomas in AOM-challenged Wt and Bcat mice (mean±s.d., n=10-11 mice, *P<0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4631784&req=5

DMM019844F4: The intestinal epithelium of Bcat mice has increased susceptibility to mutagen-induced carcinogenesis. (A) Representative methylene blue-stained large intestine of Wt and Bcat mice 5 weeks after the last of six consecutive azoxymethane (AOM) injections (scale bar=400 µm). (B) Enumeration of aberrant crypt foci in the colonic epithelium of Wt and Bcat mice (mean±s.d., n=15 mice, *P<0.05). (C) Photomicrographs of longitudinally opened and pinned out colons from Wt and Bcat mice 16 weeks after last injection of AOM (scale bar=1 cm). (D) Hematoxylin and eosin stain of a representative colonic adenoma excised from a Bcat mouse 16 weeks after the last AOM injection (scale bar=20 µm). (E) Enumeration of macroscopically visible adenomas in AOM-challenged Wt and Bcat mice (mean±s.d., n=10-11 mice, *P<0.05).
Mentions: To establish whether expression of the ΔN-Bcat transgene sensitized mice to chemical tumorigenesis, we challenged Bcat mice with the organotropic carcinogen azoxymethane (AOM). Mice were then analysed 5 and 12 weeks after the last of six consecutive AOM injections, and colons were stained in methylene blue to identify aberrant crypt foci (McLellan and Bird, 1988). Compared with Wt mice, Bcat mice harbored more aberrant crypt foci and more adenomatous polyps (Fig. 4A-C,E); however, these consistently remained well differentiated (Fig. 4D).Fig. 4.

Bottom Line: Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers.We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33(ΔN-Bcat) mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis.Collectively, our data indicate that epithelial expression of ΔN(1-131)-β-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/β-catenin pathway to facilitate and promote tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia School of Cancer Medicine, La Trobe University, Heidelberg, Victoria 3084, Australia michael.buchert@onjcri.org.au klaus-peter.janssen@lrz.tum.de.

No MeSH data available.


Related in: MedlinePlus