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Review
. 2005 Aug 25;576(1-2):132-54.
doi: 10.1016/j.mrfmmm.2004.10.014.

Mouse models expressing human carcinoembryonic antigen (CEA) as a transgene: evaluation of CEA-based cancer vaccines

Kenneth W Hance  1 , Hasan E Zeytin, John W Greiner
Affiliations
Review

Mouse models expressing human carcinoembryonic antigen (CEA) as a transgene: evaluation of CEA-based cancer vaccines

Kenneth W Hance et al. Mutat Res. .

Abstract

In recent years, investigators have carried out several studies designed to evaluate whether human tumor-associated antigens might be exploited as targets for active specific immunotherapy, specifically human cancer vaccines. Not too long ago such an approach would have been met with considerable skepticism because the immune system was believed to be a rigid discriminator between self and non-self which, in turn, protected the host from a variety of pathogens. That viewpoint has been challenged in recent years by a series of studies indicating that antigenic determinants of self have not induced absolute host immune tolerance. Moreover, under specific conditions that evoke danger signals, peptides from self-antigen can be processed by the antigen-presenting cellular machinery, loaded onto the major histocompatibility antigen groove to serve as targets for immune intervention. Those findings provide the rationale to investigate a wide range of tumor-associated antigens, including differentiation antigens, oncogenes, and tumor suppressor genes as possible immune-based targets. One of those tumor-associated antigens is the carcinoembryonic antigen (CEA). Described almost 40 years ago, CEA is a M(r) 180-200,000 oncofetal antigen that is one of the more widely studied human tumor-associated antigens. This review will provide: (i) a brief overview of the CEA gene family, (ii) a summary of early preclinical findings on overcoming immune tolerance to CEA, and (iii) the rationale to develop mouse models which spontaneously develop gastrointestinal tumors and express the CEA transgene. Those models have been used extensively in the study of overcoming host immune tolerance to CEA, a self, tumor-associated antigen, and the experimental findings have served as the rationale for the design of early clinical trials to evaluate CEA-based cancer vaccines.

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Figures

Fig. 1
Fig. 1
Immunohistochemical staining of an intestinal adenoma from an APCMin/+/CEA mouse using the anti-CEA monoclonal antibody (COL-1). Dark brown staining pattern illustrates CEA overexpression in the adenomatous tissue (10×).
Fig. 2
Fig. 2
Total number of intestinal adenomas in APCMin/+/CEA mice that received the CEA-based vaccine, non-CEA-based vaccine or vehicle alone. Each dot represents a single mouse.
Fig. 3
Fig. 3
Long-term survival of vaccinated APCMin/+/CEA and APCMin/+ mice. APCMin/+/CEA mice were vaccinated with the CEA-based (n = 12, solid circles), non-CEA-based vaccine (n = 10, solid triangles) or vehicle alone (n = 12, solid line). APCMin/+ mice (n = 5, solid squares) also received the CEA-based vaccines.
Fig. 4
Fig. 4
Histopathological (A and C) and immunohistochemical (B and D) analyses of intestinal tissues of APCMin/+/CEA mice that received the CEA-based vaccine. Panel A shows an H&E staining of ileum revealing normal architecture from an APCMin/+/CEA mouse that did not develop intestinal adenomas following CEA-based vaccinations (25×). Panel B illustrates COL-1 MAb staining (30×) showing CEA expression in the crypts of the normal intestines of the APCMin/+/CEA mouse in panel A. Panel C illustrates H&E staining of an adenoma from an APCMin/+/CEA mouse in which the CEA-based vaccine did not reduce tumor formation (25×). Areas of epithelial cell proliferation (adenomas) are identified by the arrows. Panel D shows COL-1 staining of CEA expression (20×) in an adenoma from the APCMin/+/CEA mouse, which was described in panel C.
Fig. 5
Fig. 5
Celecoxib effects on T cell COX-2 mRNA expression levels. Splenic T cells were purified from mice fed either the control diet (no celecoxib) or the 1500 ppm celecoxib-supplemented diet and incubated in the absence or presence of 2.0 μg/ml Con A for 24 h. Total RNA was isolated and the RT-PCR amplification using primer pairs for COX-2 and β-actin was carried out. Gel images were taken and COX-2 mRNA transcript levels were quantified with normalization for β-actin expression as shown in the lower panel.
Fig. 6
Fig. 6
Total number of intestinal tumors in APCMin/+/CEA mice that were fed either a control diet or a 1000 ppm celecoxib-supplemented diet. Mice also received the vehicle alone, the CEA-based vaccine or the non-CEA-based vaccine as indicated. Dots represent individual mice and horizontal lines the mean number of tumors for each treatment group. *N, total number of mice in that treatment group.
Fig. 7
Fig. 7
Long-term survival of APCMin/+/CEA mice fed either the control or 1000 ppm celecoxib-supplemented diets ± the indicated vaccine. APCMin/+/CEA mice fed the control diet were injected with the vehicle alone (n = 10, solid line, no symbol), the CEA-based vaccine (n = 11, open circles) or the non-CEA-based vaccine (n = 6, open triangles). Other groups of APCMin/+/CEA mice were fed the celecoxib-supplemented diet and also injected with the vehicle alone (n = 10, closed squares), the CEA-based vaccine (n = 12, closed circles) or the non-CEA-based vaccine (n = 7, closed triangles).
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