The role of Fas as tumor promoter

描述(申请人提供)：Fas(也称为CD95和APO-1)是一种典型的死亡受体，主要通过诱导细胞凋亡来调节免疫系统中的组织动态平衡。在癌症进展过程中，Fas经常被下调，或者使细胞具有抗凋亡能力，这增加了Fas丢失是肿瘤逃逸机制的一部分的可能性。然而，在人类肿瘤中，Fas的完全缺失是罕见的，许多癌细胞可能表达大量的Fas，并且在体外对Fas介导的细胞凋亡高度敏感。此外，癌症患者的Fas、FasL的生理配体水平经常升高。这些数据提出了一个耐人寻味的可能性，即Fas实际上可能通过其非凋亡活动促进肿瘤的生长。我们最近的数据证实，一般来说，癌细胞，无论其Fas凋亡敏感性如何，都依赖于Fas的构成活性和FasL的表达来实现最佳的生长和生存。一贯地，在卵巢癌和肝癌的小鼠模型中，Fas的丢失可以防止或减少癌症的形成，而癌细胞中FasL的消除会导致它们死亡。基于这些数据，我们建议研究三个特定目标：特定目标1：确定Fas/FasL在癌细胞生长和存活中的作用。假设：Fas是一种通用的促肿瘤受体，通过参与JNK1诱导的AP-1驱动的增殖的基础活动，这种活性对癌细胞的生存是必不可少的。具体目的2：探讨Fas与能量代谢的关系。假设：肿瘤细胞生长需要Fas和FasL调节能量代谢。具体目标3：通过阻断FasL的活性来建立治疗癌症的临床前模型。假设：抑制FasL而不是激活Fas可用于治疗卵巢癌和肝癌。这项提议的结果将有助于描绘Fas作为肿瘤促进剂的新活性，并有望导致一种具有临床相关性的治疗癌症的新方法。 公共卫生相关性：最近发现，诱导细胞凋亡的Fas及其配体FasL在组织和肿瘤细胞中介导非凋亡信号。特别是在卵巢癌和肝癌的情况下，很明显，这些活动有助于癌症的形成和生长。在这项提案中，我们将描述这些与癌症患者的治疗抵抗高度相关的新活性，并建立临床前小鼠模型，利用可溶的Fas受体来阻断这些Fas的致瘤活性。

DESCRIPTION (provided by applicant): Fas (also called CD95 and APO-1) is a prototypical death receptor that regulates tissue homeostasis primarily in the immune system through induction of apoptosis. During cancer progression, Fas is frequently downregulated, or cells are rendered apoptosis resistant, raising the possibility that loss of Fas is part of a mechanism for tumor evasion. However, complete loss of Fas is rarely seen in human cancers and many cancer cells may express large quantities of Fas, and are highly sensitive to Fas mediated apoptosis in vitro. Furthermore, cancer patients frequently have elevated levels of the physiological ligand for Fas, FasL. These data raised the intriguing possibility that Fas might actually promote the growth of tumors through its nonapoptotic activities. Our recent data have confirmed that cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas and expression of FasL for optimal growth and survival. Consistently, loss of Fas in mouse models of ovarian cancer and liver cancer prevents or reduces cancer formation, and elimination of FasL in cancer cells causes them to die. Based on these data we propose to study three specific aims: Specific Aim 1: Determine the role of Fas/FasL for the growth and survival of cancer cells. Hypothesis: Fas is a general tumor promoting receptor through a basal activity which involves JNK1 induced AP-1 driven proliferation, and this activity is essential for cancer cell survival. Specific Aim 2: Explore the connection between Fas and energy metabolism. Hypothesis: Regulation of energy metabolism by Fas and FasL is required for tumor cells to grow. Specific Aim 3: Establish preclinical models for the treatment of cancer by blocking the activity of FasL. Hypothesis: Inhibition of FasL rather than the activation of Fas can be used to treat ovarian and liver cancer. The results of this proposal will help delineate the novel activities of Fas as a tumor promoter and are expected to result in a clinically relevant and novel approach to treating cancer. PUBLIC HEALTH RELEVANCE: The apoptosis-inducing Fas and its ligand FasL have recently been recognized to mediate nonapoptotic signaling in tissues and tumor cells. Especially in the context of ovarian and liver cancer it has become clear that these activities contribute to cancer formation and growth. In this proposal we will characterize these novel activities which should be highly relevant for therapy resistance in cancer patients and establish preclinical mouse models to block these tumorigenic activities of Fas using a soluble Fas receptor.