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ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 79, 56-63 (2004)
Toxicological Sciences vol. 79 no. 1 © Society of Toxicology; all rights reserved.

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

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

{dagger} Departments of Pathology and * Surgery, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58202

Received December 9, 2003; accepted January 23, 2004

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 Cd+2 and/or As+3 are able to cause the malignant transformation of human urothelial cells. The strategy employed was to expose the nontumorigenic urothelial cell line UROtsa to long-term in vitro exposure to Cd+2 and As+3, with the endpoint 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 M Cd+2 or 1 M 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 classic transitional-cell carcinoma of the bladder. The histology of the tumor heterotransplants produced by cells malignantly transformed by As+3 was unique in that the cells displayed a prominent squamoid differentiation.

Key Words: cadmium; arsenite; arsenic; bladder cancer; UROtsa; cell culture.


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