The applicant has shown that the 3rd isoform of metallothionein (MT-3) is overexpressed in most bladder cancers and that the level of expression correlates to the grade of the tumor, being highly elevated in aggressive tumors and moderately elevated in low grade tumors and some precursor lesions. An important observation in this study was that neither MT-3 mRNA or protein was expressed in the urothelium or any other cell comprising the human bladder. These findings strongly suggest that the expression of MT-3 can be translated to provide a biomarker predictive of the early cellular alterations that progress to the development of bladder cancer. It is the applicant's hypothesis that the presence of MT-3 positive urothelial cells in the urine of patients is predictive of pre-malignant, malignant, or reoccurring malignant lesions of the urothelium. The basic science arm of this study employs the applicant's newly developed model of environmentally-induced human bladder cancer. The applicant is the first to demonstrate the direct malignant transformation of human urothelial cells with cadmium (Cd+2) or arsenic (As+3). The tumor heterotransplants generated from these transformants displayed the histology expected of transitional cell carcinoma of the bladder. In addition, tumors generated from As+3-transformed cells displayed tumors having a prominent squamous component, while those from Cd+2-transformed cells had little, or no, squamous differentiation. It is the applicant's hypothesis that these tumors will provide a platform to understand environmental influences on the development of bladder cancer and to address the fundamental problem of how chemical mixtures contribute to the development of bladder cancer.
The specific aims are: To prove the hypothesis that MT-3 expression is a biomarker for bladder cancer; To prove the hypothesis that the expression of MT-3 in Cd+2- and As+3- induced bladder cancer is similar to human bladder cancer and that expression is controlled at both the transcriptional and post-transcriptional level of gene regulation; and, To test the hypothesis that As+3-induced transitional cell cancers of the bladder have a prominent squamous component and that this fundamental departure in differentiation can be used to gain knowledge regarding the interaction of mixtures that cause environmentally-induced cancer. ? ? ?
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