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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

Histopathological findings in CEABAC20 tumors including serrated adenomatous and dysplastic morphology.A) Longitudinal section of normal colonic crypts. B) Longitudinal sections of serrated colonic crypts showing upper third of the elongated crypts (left panel), sawtooth like in-folding at the mid-crypt (middle panel) and marked branching at the crypt base (right panel). C) Cross-section of a hyperplastic crypt (red arrow) showing numerous small mucinous vacuoles. D) Longitudinal section (left panel) and cross-section (right panel) of dysplastic crypts showing elongated nuclei and nuclear stratification (red arrow). There is also evidence of myofibroblastic (spindle cell) proliferation in the lamina propria in C and D. Magnification: 400×. Staining: hematoxylin and eosin.
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pone-0001353-g007: Histopathological findings in CEABAC20 tumors including serrated adenomatous and dysplastic morphology.A) Longitudinal section of normal colonic crypts. B) Longitudinal sections of serrated colonic crypts showing upper third of the elongated crypts (left panel), sawtooth like in-folding at the mid-crypt (middle panel) and marked branching at the crypt base (right panel). C) Cross-section of a hyperplastic crypt (red arrow) showing numerous small mucinous vacuoles. D) Longitudinal section (left panel) and cross-section (right panel) of dysplastic crypts showing elongated nuclei and nuclear stratification (red arrow). There is also evidence of myofibroblastic (spindle cell) proliferation in the lamina propria in C and D. Magnification: 400×. Staining: hematoxylin and eosin.

Mentions: Histological analysis of colonic mucosa from the 3 month-old CEABAC20 mice showed a non-focal continuous mosaic of severe hyperplasia, crypt serration and dysplasia (Figure 7). Dysplastic features included colonocyte stratification, displaced nuclei with prominent nucleoli and loss of polarization.


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)

Histopathological findings in CEABAC20 tumors including serrated adenomatous and dysplastic morphology.A) Longitudinal section of normal colonic crypts. B) Longitudinal sections of serrated colonic crypts showing upper third of the elongated crypts (left panel), sawtooth like in-folding at the mid-crypt (middle panel) and marked branching at the crypt base (right panel). C) Cross-section of a hyperplastic crypt (red arrow) showing numerous small mucinous vacuoles. D) Longitudinal section (left panel) and cross-section (right panel) of dysplastic crypts showing elongated nuclei and nuclear stratification (red arrow). There is also evidence of myofibroblastic (spindle cell) proliferation in the lamina propria in C and D. Magnification: 400×. Staining: hematoxylin and eosin.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001353-g007: Histopathological findings in CEABAC20 tumors including serrated adenomatous and dysplastic morphology.A) Longitudinal section of normal colonic crypts. B) Longitudinal sections of serrated colonic crypts showing upper third of the elongated crypts (left panel), sawtooth like in-folding at the mid-crypt (middle panel) and marked branching at the crypt base (right panel). C) Cross-section of a hyperplastic crypt (red arrow) showing numerous small mucinous vacuoles. D) Longitudinal section (left panel) and cross-section (right panel) of dysplastic crypts showing elongated nuclei and nuclear stratification (red arrow). There is also evidence of myofibroblastic (spindle cell) proliferation in the lamina propria in C and D. Magnification: 400×. Staining: hematoxylin and eosin.
Mentions: Histological analysis of colonic mucosa from the 3 month-old CEABAC20 mice showed a non-focal continuous mosaic of severe hyperplasia, crypt serration and dysplasia (Figure 7). Dysplastic features included colonocyte stratification, displaced nuclei with prominent nucleoli and loss of polarization.

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