PROGNOSTIC MARKERS OF URINARY BLADDER CANCER

膀胱癌是人类疾病发病率和死亡率的重要原因。 美国。尽管人们对地球的自然历史了解很多 一般说来，膀胱癌治疗的改进受到 对个体生物攻击性的有限认识 肿瘤。肿瘤和/或早期的更好的表型特征 复发性疾病的检测将加强对 针对个别患者进行适当的治疗。肿瘤标志物的缺乏 它可以提供对肿瘤侵袭性或 促进疾病的早期发现是一个重大障碍 改进对这种疾病患者的治疗。 膀胱癌表达细胞抗原的方式通常不是 在正常的尿路上皮上发现。我们假设这些改变的细胞 可以利用抗原来确定膀胱肿瘤的表型，这将 与肿瘤生物学相关，即疾病侵袭性和反应性 去接受治疗。此外，我们假设其中至少有一部分 表达不当的抗原可能传递生长和/或转移 对膀胱癌细胞的优势。可能存在的功能蛋白质 在肿瘤细胞上传递这种优势的是整合素α6β 4和表皮生长因子受体(EGFR)。此外，其他 其功能目前尚不清楚但与 高分期膀胱癌可能提供预后信息。一个 这方面的一个例子是我们用来部分表征的一种抗原 本实验室研制了一种单抗(DD23)。 该提案包括将在5月份和5月份进行的研究。 实验室，并与合作的调查人员在 合作网络在尿路肿瘤预后评估中的应用 膀胱癌。针对我的实验室的研究将评估 关于功能分子传递转移优势的假设 包括具体目标1和2： 目的1：评价整合素α6β4的功能变化 膀胱癌。 目的2：探讨表皮生长因子受体在膀胱癌细胞运动中的作用。 这些目标将评估阿尔法6β4的改变功能 (具体地说，α6β4与 在体外和膀胱肿瘤的组织切片中 将决定EGFR在提供转移表型中的作用 通过增加细胞的运动性。 我们建议将目标3和目标4作为整个网络的协作努力： 目的3：比较膀胱冲洗与肿瘤的预后价值 标本。 目的4：肿瘤标志物在晚期膀胱癌中的应用评价。 AIMS 3和4将评估肿瘤标志物(α6β4， III型胶原、EGFR、c-erbB-2及与高表达相关的抗原 膀胱癌分期[抗体DD23])。在表面上 肿瘤，将决定是否对功能性肿瘤进行评估 组织切片上的标记提供了比这更好的信息 可从膀胱清洗中获得。这些指标的预后意义 晚期膀胱癌的标志物将在膀胱切除术中进行评估 标本。这些标志物的临床价值将在#年确定。 与现行的阶段和等级标准进行比较。

Bladder cancer is a significant cause of morbidity and mortality in the United States. Although much is known about the natural history of bladder cancer in general, improvements in therapy are hampered by a limited understanding of the biologic aggressiveness of individual tumors. Better phenotypic characterization of tumors and/or earlier detection of recurrent disease would enhance the selection of appropriate therapy for individual patients. The lack of tumor markers which could offer a reliable prediction of tumor aggressiveness or facilitate the early detection of disease is a significant obstacle to improving the treatment of patients with this disease. Bladder cancers frequently express cellular antigens in a manner not found on normal urothelium. We hypothesize that these altered cellular antigens can be exploited to define bladder tumor phenotypes which will correlate with tumor biology, i.e., disease aggressiveness and response to therapy. Furthermore, we hypothesize that at least some of these inappropriately expressed antigens may convey a growth and/or metastatic advantage to bladder cancer cells. Functional proteins which are likely to convey such an advantage on tumor cells are the integrin alpha 6 beta 4 and the epidermal growth factor receptor (EGFR). In addition, other antigens whose function is currently unknown but are associated with high stage bladder tumors are likely to offer prognostic information. An example of this is an antigen that we have partially characterized with a monoclonal antibody (DD23) developed in my laboratory. This proposal encompasses research to be performed both in may laboratory and in partnership with collaborating investigators in the Cooperative Network for Evaluation of Prognostic Markers of Urinary Bladder Cancer. Research specific to my laboratory will evaluate the hypothesis that functional molecules convey a metastatic advantage and includes specific aims 1 and 2: AIM 1: Evaluate altered function of the integrin alpha 6 beta 4 in bladder cancer. AIM 2: Evaluate the role of EGFR in bladder cancer cell motility. These aims will evaluate altered function of alpha 6 beta 4 (specifically, changes in the association of alpha 6 beta 4 with collagen VII) in vitro and in histologic sections of bladder tumors and will determine the role of EGFR in providing a metastatic phenotype through increased cell motility. We propose aims 3 and 4 as collaborative efforts thorough the Network: AIM 3: Compare the prognostic value of bladder washings with tumor specimens. AIM 4: Evaluation of tumor markers in advanced bladder cancer. Aims 3 and 4 will evaluate the role of tumor markers (alpha 6 beta 4, collagen VII, EGFR, c-erbB-2, and to an antigen associated with high stage bladder cancer [antibody DD23]) in bladder cancer. In superficial tumors, it will be determined whether the assessment of functional tumor markers on histologic sections provides superior information to that available from bladder washings. The prognostic significance of these markers in advanced bladder cancer will be evaluated on cystectomy specimens. The clinical value of these markers will be determined in comparison to the current standards of stage and grade.