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Carcinogenesis Advance Access published online on March 16, 2006
Carcinogenesis, doi:10.1093/carcin/bgl012
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received January 10, 2006
Revised February 28, 2006
Accepted March 7, 2006

CARCINOGENESIS

Zinc deficiency potentiates induction and progression of lingual and esophageal tumors in p53-deficient mice

Louise Y. Y. Fong 1 *, Yubao Jiang 1, and John L. Farber 2

1 Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
2 Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA

* To whom correspondence should be addressed.
Louise Y. Y. Fong, E-mail: Louise.Fong{at}osumc.edu


  Abstract

Upper aerodigestive tract (UADT) cancer, including oral and esophageal cancer, is an important cause of cancer deaths worldwide. Patients with UADT cancer are frequently zinc deficient and show a loss of function of the pivotal tumor suppressor gene p53. The present study examined whether zinc deficiency (ZD) in collaboration with p53 insufficiency (p53+/-) promotes lingual and esophageal tumorigenesis in mice exposed to low doses of the carcinogen 4-nitroquinoline 1-oxide. In wildtype mice, ZD significantly increased the incidence of lingual and esophageal tumors from 0% in zinc-sufficient (ZS) ZS:p53+/+ mice to ~40%. On the p53+/- background, ZD:p53+/- mice had significantly greater tumor incidence and multiplicity than ZS:p53+/- and ZD:p53+/+ mice, with a high frequency of progression to malignancy. Sixty-nine and 31 percent of ZD:p53+/- lingual and esophageal tumors, respectively, were squamous cell carcinoma versus 19% and 0% of ZS:p53+/- tumors (tongue, P=0.003; esophagus, P=0.005). Immunohistochemical analysis revealed that the increased cellular proliferation observed in preneoplastic lingual and esophageal lesions, as well as invasive carcinomas, was accompanied by overexpression of cytokeratin 14, cyclooxygenase-2, and metallothionein. In summary, a new UADT cancer model is developed in ZD:p53+/- mouse that recapitulates aspects of the human cancer and provides opportunities to probe the genetic changes intrinsic to UADT carcinogenesis and to test strategies for prevention and reversal of this deadly cancer.


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