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Carcinogenesis Advance Access published online on December 19, 2003
Carcinogenesis, doi:10.1093/carcin/bgh044
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CARCINOGENESIS

O-nitrotoluene-induced large intestinal tumors in B6C3F1 mice model human colon cancer in their molecular pathogenesis

R. C. Sills 1*, H. L. Hong 1, G. Flake 1, C. Moomaw 1, N. Clayton 1, G. A. Boorman 1, J. Dunnick 2, and T. R. Devereux 3

1 Laboratory of Experimental Pathology
2 Laboratory of General Toxicology
3 Laboratory of Molecular Carcinogenesis

* Corresponding author. E-mail: sills{at}niehs.nih.gov.

Received 22 April 2003 ; revised 8 October 2003 ; accepted 26 November 2003

Abstract

In the previous 500 two-year chemical bioassays within the National Toxicology Program, large intestinal tumors (cecal carcinomas) related to chemical exposure have not been observed in B6C3F1 mice. The recently completed o-nitrotoluene study provided the first cecal tumor response and an opportunity to evaluate the morphology and molecular profile of oncogenes and tumor suppressor genes that are relevant to humans. Morphologically, the carcinomas were gland-forming tumors lined by tall columnar epithelial cells that were positive for cytokeratin 20 and negative for cytokeratin 7. By immunohistochemistry {beta}-catenin (encoded by Catnb) protein accumulation was detected in 80% (8/10) of the cecal carcinomas, while increased cyclin D1 and p53 protein expression was detected in 73% (8/11) respectively. There was no difference in APC protein expression between normal colon and cecal carcinomas. All tumors examined exhibited mutations in exon 2 (corresponds to exon 3 in humans) in the Catnb gene. Mutations in p53 were identified in 9 of 11 carcinomas, and all were in exon 7. Analysis of the K-ras gene revealed mutations in 82% (9/11) carcinomas; all had specific G -> T transversions (Gly -> Val) at codons 10 or 12. The alterations in cancer genes and proteins found in the mouse large intestinal tumors included mutations that activate signal transduction pathways (K-ras and Catnb) and changes that disrupt the cell-cycle and bypass G1 arrest (p53, cyclin D1). These alterations, which are hallmarks of human colon cancer, likely contributed to the pathogenesis of the large intestinal carcinomas in mice following o-nitrotoluene exposure.


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