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Preclinical Studies and Early Drug Development: In Vitro and In Vivo Assays and Models |
Ohio State University, Columbus, OH
Abstract
B3
Background: Lung cancer is one of the most deadly diseases worldwide and more than 50% of lung cancers contain p53 mutations. Thousands of p53 mutant types have been identified in human lung cancers and the majority of the mutations are missense mutations. Mutant p53 can be classified into two major types, the type I (contact) mutation and type II (conformational) mutation. Important differences between these types have been established, including a higher oncogenic potential for the type II mutation, and the conservation of some wild type activity for type I. To investigate the role of types of p53 mutant in lung tumorigenesis and to create models for therapeutic and prevention studies, we established the lung specific SPC-p53 type I (273H) and type II (175H) mutant transgenic mice models, which spontaneously developed lung adenocarcinomas.Methods: To create the lung cancer animal models, the human type I p53 mutant gene (273H, Arg to His at codon 273) or the type II p53 mutant gene (175H, Arg to His at codon 175) was placed under the control of the human surfactant protein C (SPC) promoter to selectively express the mutant gene in lung tissue. Transgenic mice were generated by microinjection of a 6.7-kb fragment of the SPC-p53 construct into the pro-nuclei of FVB/N mouse zygotes.Results: Two type I founder mice were identified. One founder (a female), failed to transmit the transgene to offspring and the line of the type I (SPC-p53/273H) transgenic mice was established from the second founder (a male). Four type II transgenic founders were identified; 3 females and 1 male. Two female mice did not pass the transgene, whereas the other two passed the transgene to the F1 generation, permitting to establish the type II (SPC-p53/175H) transgenic mice. Immunohistochemistry and Western blot analysis showed that both p53(175H) and p53(273H) expressed in a lung specific manner.To evaluate lung tumor incidence and age of onset, cohorts of type I transgenic mice (n=122) were sacrificed at different age groups. Lung tumors were observed in one mouse in the 4-6 month group (n=21), one mouse in the 7-9 month group (n=20), two mice in the 10-12 month group (n=34), and thirteen mice in the 13-15 month group (n=47). Among 160 of type II mice were evaluated, one tumor was observed in the 4-6 month group (n=14), six tumor bearing mice in the 7-9 month group (n=23), 14 mice in the 10-12 month group (n=59) and twenty mice in the 13-15 month group (n=64). All tumors were identified histopathologically as adenocarcinomas.Cohorts of non-transgenic littermates (n=109) were also evaluated for tumor formation at the same ages as the transgenic animals. No tumors were observed in the 4-6 (n=20) and 7-9 month groups (n=22), while lung tumors were detected in two mice each in the 10-12 (n = 31) and 13-15 (n=35) month groups.Conclusions: Overall, the type II mutant p53 transgenic mice have an earlier lung tumor onset and higher lung tumor rate as compared to the type I and wildtype control mice at all time points. The type I mice have a significant higher lung tumor rate as compared to wildtype controls at age of 13-15 months. These lung cancer animal models develop discrete single lung andenocarcinoma, and should provide valuable models for evaluating the effect of a mutant type on response to treatment interventions.
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