Novel mouse model for carcinoembryonic antigen-based therapy

Abstract

Many novel cancer therapies, including immunotherapy and gene therapy, are specifically targeted to tumor-associated molecules, among which carcinoembryonic antigen (CEA) represents a popular example. Discrepancies between preclinical experimental data in animal models and clinical outcome in terms of therapeutic response and toxicity, however, often arise. Preclinical testing can be compromised by the lack of CEA and other closely related human CEA family members in rodents, which lack analogous genes for most human CEA family members. Here, we report the construction of a transgenic mouse with a 187-kb human bacterial artificial chromosome (CEABAC) that contains part of the human CEA family gene cluster including complete human CEA (CEACAM5), CEACAM3, CEACAM6, and CEACAM7 genes. The spatiotemporal expression pattern of these genes in the CEABAC mice was found to be remarkably similar to that of humans. This novel mouse will ensure better assessment than previously utilized models for the preclinical testing of CEA-targeted therapies and perhaps allow the testing of CEACAM6, which is overexpressed in many solid tumors and leukemias, as a therapeutic target. Moreover, expression of CEA family genes in gastrointestinal, breast, hematopoietic, urogenital, and respiratory systems could facilitate other clinical applications, such as the development of therapeutic agents against Neisseria gonorrhoeae infections, which use CEA family members as major receptors.

Distribution and surfactant association of carcinoembryonic cell adhesion molecule 6 in human lung

“…1H), we observed increased intensity and distribution of CEACAM6 immunoreactivity in the hyperplastic alveolar epithelium that develops in response to injury, whereas, in adult lung, CEACAM6 is expressed in only a subpopulation of type II cells. It is possible that CEACAM6, via its antiapoptotic activity for lung epithelial cells (24), promotes cell proliferation in response to lung injury, while also contributing to innate immune defense, along with other lung proteins, such as SP-A and SP-D. Our laboratory is currently examining CEACAM6 expression in additional sections of injured infant lung and in bleomycin-injured lungs of transgenic mice expressing human CEACAM6 (12).…”

“…PCR and agarose gel electrophoresis was performed on 70 ng of cDNA from each sample, plus a no cDNA control (21, 25, 29 cycles) using an annealing temperature of 55°C in a PT-200 Peltier Thermal Cycler (MJ Research, Waltham, MA). Primer sequences used are specific for human CEACAM6 (12) with an expected product of 353 bp: 5= primer ϭ 5=-TACTCAGCGTCAAAAGGAAC-3= and 3= primer ϭ 5=-AGAGACTGTGATCATCGTGA-3=.…”

Deletion of the carcinoembryonic antigen-related cell adhesion molecule 1 (Ceacam1) gene contributes to colon tumor progression in a murine model of carcinogenesis

“…Recent studies have also suggested that CEACAM1 and CEACAM6 also play a significant role in colonic tumor development (Neumaier et al, 1993;Nollau et al, 1997a, b;Scholzel et al, 2000;Jantscheff et al, 2003). As the mouse neither expresses CEA nor CEACAM6 and relies for most of its CEA-related functions on the expression of CEACAM1, studies investigating the role of these proteins depend on the generation of adequate transgenic mouse models (Chan and Stanners, 2004) or the availability of mice deficient for CEACAM1. In this manuscript, we describe the generation of the Ceacam1À/À mouse.…”

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

“…Moreover, CEACAM1 is widely expressed on lymphocytes, and CEACAM1-induced signaling can influence immune cell activation (28)(29)(30)(31)(32)(33)(34)(35), potentially providing a mechanism for immune evasion by N. gonorrhoeae. While no study to date has looked at CEACAM expression within the male urethra, a transgenic mouse line expressing human CEACAMs in a manner that closely reflects the spatiotemporal expression pattern in humans expresses CEACAM5 on the urethral mucosal surface (36).…”