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3亚型在大多数膀胱癌中过表达，并且表达水平与肿瘤的级别相关，在侵袭性肿瘤中高度升高，在低级别肿瘤和一些前体病变中中度升高。本研究的一个重要观察结果是，MT-3 mRNA或蛋白均未在尿路上皮或任何其他构成人类膀胱的细胞中表达。这些发现强烈表明，MT-3的表达可以被翻译为一种生物标志物，预测膀胱癌发展过程中的早期细胞改变。申请人的假设是，患者尿液中存在MT-3阳性尿路上皮细胞可预测尿路上皮的恶性病变前期、恶性或复发性恶性病变。本研究的基础科学部分采用申请人新开发的环境诱导人类膀胱癌模型。申请人是第一个证明镉（Cd+2）或砷（As+3）直接恶性转化人尿路上皮细胞的人。由这些转化体产生的肿瘤异种移植表现出膀胱移行细胞癌的组织学特征。此外，由As+3转化的细胞产生的肿瘤具有明显的鳞状成分，而由Cd+2转化的细胞产生的肿瘤很少或没有鳞状分化。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。具体目的是：证明MT-3表达是膀胱癌的生物标志物的假设；证明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，且表达在基因调控的转录和转录后水平受到控制；并且，为了验证As+3诱导的膀胱移行细胞癌具有突出的鳞状成分的假设，并且这种分化的基本背离可用于获得有关导致环境诱导癌症的混合物相互作用的知识。

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.