Date of Award

January 2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

First Advisor

Scott H. Garrett

Abstract

Environmental agents are common causes of bladder cancer. Specifically, arsenic (As3+) and cadmium (Cd2+) are known carcinogens implicated in the development of bladder cancer. Previous studies from our laboratory have shown that As3+ and Cd2+ can cause malignant transformation of normal immortalized bladder urothelial cells, which can form tumors when injected subcutaneous or intraperitoneal into nude mice. Microarray analysis of repeated metal transformation in parallel revealed that N-cadherin was the most upregulated gene in As3+ transformants, and a top induced gene in Cd2+-transformed cells. The switch from E-cadherin to N-cadherin is a well-known indicator of the epithelial-to-mesenchymal transition occurring in bladder cancer. Further, N-cadherin upregulation is correlated with tumor stage, increased recurrence, and decreased survival in patients. While the factors mediating the decrease in E-cadherin expression are well-established, little is known of the factors regulating the increase in N-cadherin expression. The goal of the present study was to determine how As3+ and Cd2+ regulate N-cadherin expression, whether this expression is maintained in heterotransplant models, and if N-cadherin is promoting the epithelial-to-mesenchymal transition in As3+- and Cd2+-transformed UROtsa cells in vitro. This work has demonstrated that N-cadherin is induced in As3+- and Cd2+-transformed UROtsa cell lines, and that the expression is maintained in intraperitoneal, but not subcutaneous, tumor xenografts. Further, tumor-initiating cells derived from transformed UROtsa cells did not express N-cadherin. This suggests that tumor microenvironment and heterogeneity of cell populations are important factors for the use of animal models in cancer research. The As3+ and Cd2+ UROtsa cell lines represent the initial phases of EMT in bladder cancer, and may demonstrate a unique EMT pathway specific to heavy metal carcinogens. Transcriptional regulation of N-cadherin, which is mostly unknown, may be elucidated by the investigation of the transcription factor Twist and epigenetic regulation, particularly histone acetylation.

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