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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 膀胱尿路上皮癌约占人类所有癌症死亡的5%。 目前的治疗延长了复发时间，但不改变疾病生存率。 自1976年以来，牛分枝杆菌（MycobacteriumbovisvacillusCalmette-Guerin）（BCG）已经越来越成功地用于治疗浅表性膀胱癌，并且是这种肿瘤实体的治疗选择。 令人惊讶的是，抗肿瘤效应机制仍然难以捉摸。 BCG免疫治疗导致大量局部免疫应答，其特征在于诱导Th-1细胞因子（例如，IL-2、IL-12、IFN-γ），以及粒细胞和单核细胞流入膀胱壁。 我们对在这种临床环境中产生的IFN-γ特别感兴趣，因为IFN-γ刺激多种免疫细胞类型的TNF相关凋亡诱导配体（TRAIL）的表达，TRAIL是TNF家族成员，其在多种肿瘤细胞类型中诱导凋亡，但对正常细胞具有很少或没有细胞毒性。 我们小组最近的研究首次证明了TRAIL在BCG治疗期间被诱导。 尿TRAIL水平与有效治疗相关，表明与抗肿瘤活性有关。 此外，在检查的时间段内（滴注后3-5小时），TRAIL在排出的中性粒细胞上表达。 这些研究者假设，BCG治疗浅表性膀胱癌诱导浸润性炎性细胞，特别是嗜中性粒细胞上的TRAIL表达，这是有利的治疗结果所必需的效应分子。 因此，该提案描述了将评估来自接受BCG治疗的膀胱癌患者的临床样品以证实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.