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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh086
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 9, 2003; accepted January 23, 2004
© 2004 Society of Toxicology

Endocrine Toxicology

Inorganic Cadmium- and Arsenite-Induced Malignant Transformation of Human Bladder Urothelial Cells

Donald A. Sens 1, Seongmi Park 2, Volkan Gurel 2, Mary Ann Sens 2, Scott H. Garrett 2, and Seema Somji 2*

1 Department of Surgery, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202
2 Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202

* To whom correspondence should be addressed. E-mail: ssomji{at}medicine.nodak.edu.


  Abstract

Arsenic and cadmium (Cd+2) are human carcinogens and epidemiological studies have implicated both pollutants in the development of urinary bladder cancer. Despite this epidemiological base, it is unknown if either Cd+2 or arsenite (As+3) can directly cause the malignant transformation of human urothelial cells. The goal of this study was to determine if either Cd+2, As+3, or both, are able to cause the malignant transformation of human urothelial cells. The strategy employed was to expose the non-tumorigenic urothelial cell line, UROtsa, to long term in vitro exposure to Cd+2 and As+3, with the end point being the ability of the cells to form colonies in soft agar and tumors when heterotransplanted into nude mice. It was demonstrated that a long-term exposure to either 1 µM Cd+2 or As+3 resulted in the selection of cells that were able to form colonies in soft agar and tumors when heterotransplanted into nude mice. The histology of the tumor heterotransplants produced by UROtsa cells malignantly transformed by Cd+2 had epithelial features consistent with those of a classical transitional cell carcinoma of the bladder. The histology of the tumor heterotransplants produced by cells malignantly transformed by As+3 were unique in that they displayed a prominent squamoid differentiation.

Key Words: Cadmium, Arsenite, Arsenic, Bladder Cancer, UROtsa, Cell Culture .


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