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Colorectal hyperplasia and dysplasia due to human carcinoembryonic antigen (CEA) family member expression in transgenic mice.

Chan CH, Camacho-Leal P, Stanners CP - PLoS ONE (2007)

Bottom Line: The colonocyte surface level of integrin alpha5 and the activation of AKT increased progressively with the expression levels of CEA/CEACAM6.Colonic crypts showed a progressive increase in colonocyte proliferation, an increase in crypt fission, and a strong inhibition of both differentiation and anoikis/apoptosis.All transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia and serrated adenomatous morphology.

View Article: PubMed Central - PubMed

Affiliation: McGill Cancer Centre, Department of Biochemistry, McGill University, Montréal, Québec, Canada. carlos.chan@mcgill.ca

ABSTRACT
CEA and CEACAM6 are immunoglobulin family intercellular adhesion molecules that are up-regulated without structural mutations in approximately 70% of human cancers. Results in in vitro systems showing tumorigenic effects for these molecules suggest that this correlation could indicate an instrumental role in tumorigenesis. To test whether this applies in vivo, transgenic mice harboring 187 kb of the human genome containing four CEA family member genes including the CEA and CEACAM6 genes were created and their copy numbers increased by mating until colonocyte expression levels reached levels seen in human colorectal carcinomas. The colonocyte surface level of integrin alpha5 and the activation of AKT increased progressively with the expression levels of CEA/CEACAM6. Colonic crypts showed a progressive increase in colonocyte proliferation, an increase in crypt fission, and a strong inhibition of both differentiation and anoikis/apoptosis. All transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia and serrated adenomatous morphology. These results suggest that up-regulated non-mutated adhesion molecules could have a significant instrumental role in human cancer.

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Related in: MedlinePlus

Massive colonic tumors in 3 month-old CEABAC20 mice.A) Cross sections of colon; note the much larger size of the CEABAC20 vs WT colons. B) Dramatic increase of colon mass and absence of fecal pellets in CEABAC20 over the entire colon. C) Colonic crypts; note the dramatic lengthening of intensely stained crypts in CEABAC20. Magnification: 40× (A), 100× (C). Staining: hematoxylin (A, C).
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pone-0001353-g006: Massive colonic tumors in 3 month-old CEABAC20 mice.A) Cross sections of colon; note the much larger size of the CEABAC20 vs WT colons. B) Dramatic increase of colon mass and absence of fecal pellets in CEABAC20 over the entire colon. C) Colonic crypts; note the dramatic lengthening of intensely stained crypts in CEABAC20. Magnification: 40× (A), 100× (C). Staining: hematoxylin (A, C).

Mentions: A progressive shift with CEABAC dose towards a deranged tissue architecture featuring more mucosal tissue and less luminal space was seen in cross sections of colons from 3 week-old transgenic mice (Figure 4D). This effect became quite dramatic in CEABAC20 mice by 3 months of age, where 100% of the mice showed grossly enlarged colons with crypts up to 10 times normal length and with virtually no central lumen (Figure 6). These mice were considerably smaller than normal (Figure 1B), had persistent diarrhea and rectal bleeding, and died prematurely from the first weeks of life to about 9 months maximum; all animals died with rectal prolapse. The effects were more pronounced in female, especially pregnant, mice than in males.


Colorectal hyperplasia and dysplasia due to human carcinoembryonic antigen (CEA) family member expression in transgenic mice.

Chan CH, Camacho-Leal P, Stanners CP - PLoS ONE (2007)

Massive colonic tumors in 3 month-old CEABAC20 mice.A) Cross sections of colon; note the much larger size of the CEABAC20 vs WT colons. B) Dramatic increase of colon mass and absence of fecal pellets in CEABAC20 over the entire colon. C) Colonic crypts; note the dramatic lengthening of intensely stained crypts in CEABAC20. Magnification: 40× (A), 100× (C). Staining: hematoxylin (A, C).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2131779&req=5

pone-0001353-g006: Massive colonic tumors in 3 month-old CEABAC20 mice.A) Cross sections of colon; note the much larger size of the CEABAC20 vs WT colons. B) Dramatic increase of colon mass and absence of fecal pellets in CEABAC20 over the entire colon. C) Colonic crypts; note the dramatic lengthening of intensely stained crypts in CEABAC20. Magnification: 40× (A), 100× (C). Staining: hematoxylin (A, C).
Mentions: A progressive shift with CEABAC dose towards a deranged tissue architecture featuring more mucosal tissue and less luminal space was seen in cross sections of colons from 3 week-old transgenic mice (Figure 4D). This effect became quite dramatic in CEABAC20 mice by 3 months of age, where 100% of the mice showed grossly enlarged colons with crypts up to 10 times normal length and with virtually no central lumen (Figure 6). These mice were considerably smaller than normal (Figure 1B), had persistent diarrhea and rectal bleeding, and died prematurely from the first weeks of life to about 9 months maximum; all animals died with rectal prolapse. The effects were more pronounced in female, especially pregnant, mice than in males.

Bottom Line: The colonocyte surface level of integrin alpha5 and the activation of AKT increased progressively with the expression levels of CEA/CEACAM6.Colonic crypts showed a progressive increase in colonocyte proliferation, an increase in crypt fission, and a strong inhibition of both differentiation and anoikis/apoptosis.All transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia and serrated adenomatous morphology.

View Article: PubMed Central - PubMed

Affiliation: McGill Cancer Centre, Department of Biochemistry, McGill University, Montréal, Québec, Canada. carlos.chan@mcgill.ca

ABSTRACT
CEA and CEACAM6 are immunoglobulin family intercellular adhesion molecules that are up-regulated without structural mutations in approximately 70% of human cancers. Results in in vitro systems showing tumorigenic effects for these molecules suggest that this correlation could indicate an instrumental role in tumorigenesis. To test whether this applies in vivo, transgenic mice harboring 187 kb of the human genome containing four CEA family member genes including the CEA and CEACAM6 genes were created and their copy numbers increased by mating until colonocyte expression levels reached levels seen in human colorectal carcinomas. The colonocyte surface level of integrin alpha5 and the activation of AKT increased progressively with the expression levels of CEA/CEACAM6. Colonic crypts showed a progressive increase in colonocyte proliferation, an increase in crypt fission, and a strong inhibition of both differentiation and anoikis/apoptosis. All transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia and serrated adenomatous morphology. These results suggest that up-regulated non-mutated adhesion molecules could have a significant instrumental role in human cancer.

Show MeSH
Related in: MedlinePlus