Keratin 6 expression correlates to areas of squamous differentiation in multiple independent isolates of As(+3)-induced bladder cancer

• Published in: Journal of applied toxicology 2010-07, Vol.30 (5), p.416
• Main Authors: Cao, Ling, Zhou, Xu Dong, Sens, Mary Ann, Garrett, Scott H, Zheng, Yun, Dunlevy, Jane R, Sens, Donald A, Somji, Seema
• Format: Article
• Language: English
• Subjects: Animals; Arsenicals; Biomarkers, Tumor; Carcinogens - toxicity; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Carcinoma, Transitional Cell - pathology; Cell Line, Transformed; Cell Line, Tumor; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Keratin-6 - genetics; Keratin-6 - metabolism; Mice; Mice, Nude; Neoplasm Transplantation; Oxides - toxicity; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urothelium - drug effects; Urothelium - metabolism; Urothelium - pathology
• ISSN: 1099-1263
• DOI: 10.1002/jat.1513

This laboratory has shown that arsenite (As(+3)) exposure can cause the malignant transformation of the UROtsa human urothelial cell line. This single isolate formed subcutaneous tumors with a histology similar to human urothelial cell carcinoma. The tumors also displayed areas of squamous differentiation of the urothelial cells, an infrequent but known component of human bladder cancer. In the present study, five additional independent isolates of As(+3)-transformed urothelial cells were isolated and each was shown to produce subcutaneous urothelial cell tumors with a characteristic histology very similar to those described in the initial report. That there were underlying phenotypic differences in the six independent isolates was demonstrated when they were assessed for their ability to form tumors within the peritoneal cavity. It was shown that two isolates could form hundreds of small peritoneal tumor nodules, one isolate a moderate number of tumor nodules, and three isolates no or only one tumor nodule. The peritoneal tumors were also characterized for their degree of squamous differentiation of the urothelial cells and, while areas of squamous differentiation could be found, such differentiation was substantially reduced compared to subcutaneous tumors. Immunostaining for keratin 6 was tested as a potential marker for malignant urothelial cells that had undergone squamous differentiation. Keratin 6 was shown to consistently stain only cells having some evidence of squamous differentiation. Keratin 16 was shown to follow the staining pattern of keratin 6. The isolates and tumor heterotransplants were all examined for keratin 6, 16 and 17 mRNA and protein expression.