TRAIL: A MECHANISM FOR BCG-INDUCED ANTI-TUMOR ACTIVITY IN BLADDER CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 膀胱尿路上皮癌约占人类所有癌症死亡的5%。目前的治疗方法延长了复发的时间，但并不能改变疾病的存活率。自1976年以来，卡介苗(BCG)一直被用于治疗浅表性膀胱癌，取得了越来越大的成功，并成为这种肿瘤实体的首选治疗方法。令人惊讶的是，抗肿瘤效应机制仍然难以捉摸。卡介苗免疫治疗导致大量局部免疫反应，其特征是诱导尿液和膀胱组织中Th-1细胞因子(如IL-2、IL-12、干扰素-γ)的表达，以及粒细胞和单个核细胞进入膀胱壁。我们特别感兴趣的是在这种临床环境下产生的干扰素-γ，因为干扰素-γ刺激多种免疫细胞类型表达肿瘤坏死因子相关的凋亡诱导配体(TRAIL)，这是一种肿瘤坏死因子家族成员，可诱导多种肿瘤细胞类型的凋亡，但对正常细胞几乎没有细胞毒作用。我们小组最近的研究首次证明TRAIL是在卡介苗治疗过程中产生的。尿TRAIL水平与有效治疗相关，提示与抗肿瘤活性有关。此外，在检测的时间段(滴注后3-5H)，TRAIL在排空的中性粒细胞上表达。这些研究人员假设，卡介苗治疗浅表性膀胱癌诱导了浸润性炎症细胞上TRAIL的表达，特别是中性粒细胞，这是获得良好治疗结果所必需的效应分子。因此，这项提案描述了将评估接受卡介苗治疗的膀胱癌患者的临床样本以证实TRAIL的作用的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Urothelial carcinoma of the bladder accounts for approximately 5% of all cancer deaths in humans. Current treatments extend time to recurrence but do not alter disease survival. since 1976, Mycobacterium bovis vacillus Calmette-Guerin (BCG) has been used with increased success to treat superficial bladder cancer, and is the treatment of choice for this tumor entity. Surprisingly, the antitumor effector mechanisms remain elusive. BCG immunotherapy results in a massive local immune response characterized by the induced expression of Th-1 cytokines (e.g., IL-2, IL-12, IFN-y) in the urine and bladder tissue, and by an influx of granulocytes and mononuclear cells into the bladder wall. We are especially interested in IFN-y produced in this clinical setting, because IFN-y stimulates on multiple immune cell types the expression of TNF-related apoptosis-inducing ligand (TRAIL), a TNF family member that induces apoptosis in a variety of tumor cell types but has little or no cytotoxicity against normal cells. Recent studies by our group demonstrated for the first time that TRAIL is induced during BCG treatment. Urine TRAIL levels correlated with effective therapy, suggesting a link to antitumor activity. Moreover, TRAIL was expressed on voided neutrophils during the time period examined (3-5 H post instillation). These investigators hypothesize that BCG treatment of superficial bladder cancer induces TRAIL expression on infiltrating inflammatory cells, especially neutorphils, which is a necessary effector molecule for a favorable therapeutic outcome. Thus, this proposal describes studies that will evaluate clinical samples from bladder cancer patients undergoing BCG therapy to substantiate the role of TRAIL.