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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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Hyperproliferation in CEABAC mouse colonic epithelium at 3 weeks of age.A) Extension of the proliferative zones in colonic crypts is shown for both CEABAC10 and CEABAC20 by PCNA staining. Lengthening of crypts, poor cryptal alignment, increase of peri-cryptal stroma, and elongation of nuclei are noted in CEABAC20 mice, indicating hyperplastic changes. Arrow shows an example of crypt fission used to calculate percent crypt fission for C. B) Proliferation indices estimated by PCNA staining in A show significant increases for both CEABAC10 and CEABAC20 from WT mice (P<0.0001). C) Percent crypt fission plotted against transgene copy-number shows a linear curve with a correlation coefficient of 0.977; each data point is significantly different from the others (P<0.0001). D) Cross sections of colons show increasing epithelial content with increasing CEABAC transgene copy number (i.e. CEA/CEACAM6 expression levels). Magnification: 400× (A), 100× (D). Staining: hematoxylin. Error bars represent standard errors of the mean (N = 9). WT denotes wild-type littermate.
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pone-0001353-g004: Hyperproliferation in CEABAC mouse colonic epithelium at 3 weeks of age.A) Extension of the proliferative zones in colonic crypts is shown for both CEABAC10 and CEABAC20 by PCNA staining. Lengthening of crypts, poor cryptal alignment, increase of peri-cryptal stroma, and elongation of nuclei are noted in CEABAC20 mice, indicating hyperplastic changes. Arrow shows an example of crypt fission used to calculate percent crypt fission for C. B) Proliferation indices estimated by PCNA staining in A show significant increases for both CEABAC10 and CEABAC20 from WT mice (P<0.0001). C) Percent crypt fission plotted against transgene copy-number shows a linear curve with a correlation coefficient of 0.977; each data point is significantly different from the others (P<0.0001). D) Cross sections of colons show increasing epithelial content with increasing CEABAC transgene copy number (i.e. CEA/CEACAM6 expression levels). Magnification: 400× (A), 100× (D). Staining: hematoxylin. Error bars represent standard errors of the mean (N = 9). WT denotes wild-type littermate.

Mentions: What are the cellular consequences in vivo of the increase in cell surface density of integrin α5 and the consequent downstream molecular activation events that arise from the presence of the CEABAC transgenes in colonocytes? A transgene copy number-dependent increase in the colonocyte proliferation index indicated by PCNA staining was observed in colonic crypts from 3 week-old CEABAC transgenics relative to WT littermates (Figure 4B). This was due to the progressive extension (with CEABAC dose) of the proliferative zone towards the upper parts of the crypts reaching the full length of the crypts in CEABAC20 mice (Figure 4A). This effect resulted in an overall increase in the length of the CEABAC20 crypts (Figures 4A and 5A). There was also a marked CEABAC dose-dependent increase in the incidence of crypt fission (Figure 4C), the process whereby new crypts are created in the colon [31].


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)

Hyperproliferation in CEABAC mouse colonic epithelium at 3 weeks of age.A) Extension of the proliferative zones in colonic crypts is shown for both CEABAC10 and CEABAC20 by PCNA staining. Lengthening of crypts, poor cryptal alignment, increase of peri-cryptal stroma, and elongation of nuclei are noted in CEABAC20 mice, indicating hyperplastic changes. Arrow shows an example of crypt fission used to calculate percent crypt fission for C. B) Proliferation indices estimated by PCNA staining in A show significant increases for both CEABAC10 and CEABAC20 from WT mice (P<0.0001). C) Percent crypt fission plotted against transgene copy-number shows a linear curve with a correlation coefficient of 0.977; each data point is significantly different from the others (P<0.0001). D) Cross sections of colons show increasing epithelial content with increasing CEABAC transgene copy number (i.e. CEA/CEACAM6 expression levels). Magnification: 400× (A), 100× (D). Staining: hematoxylin. Error bars represent standard errors of the mean (N = 9). WT denotes wild-type littermate.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2131779&req=5

pone-0001353-g004: Hyperproliferation in CEABAC mouse colonic epithelium at 3 weeks of age.A) Extension of the proliferative zones in colonic crypts is shown for both CEABAC10 and CEABAC20 by PCNA staining. Lengthening of crypts, poor cryptal alignment, increase of peri-cryptal stroma, and elongation of nuclei are noted in CEABAC20 mice, indicating hyperplastic changes. Arrow shows an example of crypt fission used to calculate percent crypt fission for C. B) Proliferation indices estimated by PCNA staining in A show significant increases for both CEABAC10 and CEABAC20 from WT mice (P<0.0001). C) Percent crypt fission plotted against transgene copy-number shows a linear curve with a correlation coefficient of 0.977; each data point is significantly different from the others (P<0.0001). D) Cross sections of colons show increasing epithelial content with increasing CEABAC transgene copy number (i.e. CEA/CEACAM6 expression levels). Magnification: 400× (A), 100× (D). Staining: hematoxylin. Error bars represent standard errors of the mean (N = 9). WT denotes wild-type littermate.
Mentions: What are the cellular consequences in vivo of the increase in cell surface density of integrin α5 and the consequent downstream molecular activation events that arise from the presence of the CEABAC transgenes in colonocytes? A transgene copy number-dependent increase in the colonocyte proliferation index indicated by PCNA staining was observed in colonic crypts from 3 week-old CEABAC transgenics relative to WT littermates (Figure 4B). This was due to the progressive extension (with CEABAC dose) of the proliferative zone towards the upper parts of the crypts reaching the full length of the crypts in CEABAC20 mice (Figure 4A). This effect resulted in an overall increase in the length of the CEABAC20 crypts (Figures 4A and 5A). There was also a marked CEABAC dose-dependent increase in the incidence of crypt fission (Figure 4C), the process whereby new crypts are created in the colon [31].

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