Susceptibility of Heterozygous and Nullizygous p53 Knockout Mice to Chemical Carcinogens: Tissue Dependence and Role of p53 Gene Mutations

Abstract

Mutations of the p53 tumor suppressor gene constitute one of the most frequent molecular changes in a wide variety of human cancers and mice deficient in p53 have recently attracted attention for their potential to identify chemical genotoxins. In this article, we review the data on the susceptibility of p53 nullizygote (-/-), heterozygote (+/-), and wild type (+/+) mice to various carcinogens. Induction of esophageal and tongue squamous cell carcinomas (SCCs) by methyl-n-amylnitrosamine was shown to be increased in p53 (+/-) mice, in addition to the high sensitivity shown by p53 (-/-) littermates. N,N-dibutylnitrosamine (DBN) treatment also caused more tumor development in p53 (+/-) than wild-type mice, as with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the urinary bladder. In addition, p53 (+/-) heterozygotes proved more sensitive than wild type littermates to the induction of stromal cell tumors like hemangiomas/hemangiosarcomas by N-bis(2-hydroxypropyl)nitrosamine (BHP) or lymphomas and fibrosarcomas with other carcinogens. Analysis of exons 5-8 of the p53 gene demonstrated mutations in approximately one half of the lesions. With N-methyl-N-nitrosourea, preneoplastic lesions of the stomach, pepsinogen altered pyloric glands (PAPG), and a gastric adenocarcinoma, were found after only 15 weeks in p53 (-/-) mice, although there was no significant difference in the incidence of gastric tumors between p53 (+/+) and (+/-) mice in the longer-term. Regarding colon carcinogenicity, adenocarcinomas were observed limited to 1, 2-dimethylhydrazine treated p53 (-/-) mice in the short term, but again, no significant difference was evident between the p53 (+/+) and (+/-) cases at the end of the study. Furthermore, diethylnitrosamine or aminophenylnorharman treated p53 (+/-) mice did not demonstrate elevated susceptibility to tumors in the liver. With BHP, which induces tumors in multiple organs, p53 (+/-) mice were not more statistically sensitive with regard to lung tumor development than p53 (+/+). Of the malignant tumors examined in p53 (+/+) and (+/-) mice, as many as 10% demonstrated mutations in the p53 gene. These results suggest that p53 may not be a direct target for mouse adenomas/adenocarcinomas, but rather plays an important role as a gatekeeper in their genesis. In contrast p53 itself is frequently mutated in squamous, urothelial, or stromal tumors with a clear order of susceptibility: p53 (-/-) > p53 (+/-) > p53 (+/+) mice. p53 (-/-) mice are versatile animals for carcinogenicity testing, despite their disadvantage of a high background of spontaneous tumor development, and tissue dependence must be taken into account when exposing p53 (+/-) mice to chemical carcinogens.