Metallothionein Isoform 3 as a Urinary Marker for Bladder Cancer

描述（由申请人提供）：申请人已经证明金属硫蛋白（MT-3）的第三种亚型在大多数膀胱癌中过表达，并且表达水平与肿瘤分级相关，在侵袭性肿瘤中高度升高，在低级别肿瘤和一些前驱病变中中度升高。本研究中的一个重要观察结果是，MT-3 mRNA或蛋白质在尿路上皮或构成人膀胱的任何其他细胞中均不表达。这些发现有力地表明，MT-3的表达可以被翻译为提供预测进展到膀胱癌发展的早期细胞改变的生物标志物。申请人的假设是，患者尿液中MT-3阳性尿路上皮细胞的存在预示尿路上皮的癌前病变、恶性病变或复发性恶性病变。本研究的基础科学部分采用了申请人新开发的环境诱导的人类膀胱癌模型。申请人首次证明镉（Cd+2）或砷（As+3）可直接导致人尿路上皮细胞恶性转化。从这些转化体产生的肿瘤异源移植物显示膀胱移行细胞癌的预期组织学。此外，从As+3转化细胞产生的肿瘤显示具有突出的鳞状成分的肿瘤，而从Cd+2转化细胞产生的肿瘤几乎没有或没有鳞状分化。申请人的假设是，这些肿瘤将提供一个平台，以了解环境对膀胱癌发展的影响，并解决化学混合物如何促进膀胱癌发展的基本问题。具体目标是：证实MT-3表达是膀胱癌的生物标志物的假说：证实MT-3在Cd+2和As+3诱导的膀胱癌中的表达与人膀胱癌相似，其表达受转录和转录后水平基因调控的假说;并且，在本发明中，为了检验As+3-诱导的膀胱移行细胞癌具有显著的鳞状成分，并且这种分化的根本偏离可用于获得关于混合物的相互作用的知识，导致环境诱发的癌症。

DESCRIPTION (provided by applicant): 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.