Increased colon tumor susceptibility in azoxymethane treated CEABAC transgenic mice

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Human carcinoembryonic antigen (CEA) and CEACAM6 are overexpressed in many cancers, suggesting a role in tumorigenesis.
• In vitro studies support the involvement of CEA and CEACAM6 in cancer development.
• Investigating in vivo roles is crucial, but mice lack homologous CEACAM genes.

Purpose of the Study:

• To investigate the in vivo role of human glycophosphatidyl inositol (GPI)-anchored CEACAM family genes in colon tumorigenesis.
• To establish a mouse model that accurately reflects human colon cancer development associated with CEACAM expression.

Main Methods:

• Constructed transgenic mice (CEABAC) carrying a human CEACAM gene locus (CEA, CEACAM6, CEACAM7).
• Induced colon tumors in CEABAC mice and wild-type littermates using azoxymethane (AOM).
• Analyzed tumor load, CEACAM expression levels, spatial patterns, and beta-catenin mutations.

Main Results:

• CEABAC transgenics exhibited over a 2-fold increase in mean tumor load compared to wild-type mice.
• Colon tumor cells showed significant increases in CEA (2-fold) and CEACAM6 (20-fold) expression.
• Aberrant CEA/CEACAM6 expression patterns were observed in normal crypts near tumors, mirroring human colon cancer.
• A modest increase in beta-catenin mutations was found in AOM-induced CEABAC tumors.

Conclusions:

• Expression of human GPI-anchored CEACAM family genes in mice predisposes them to colon tumor development.
• These genes contribute to acquiring or retaining mutations essential for sporadic colon tumor formation.
• The CEABAC mouse model effectively recapitulates key aspects of human colon tumorigenesis related to CEACAMs.