The role of Fas as tumor promoter

描述（由申请人提供）：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稳态。在癌症进展过程中，Fas经常被下调，或者细胞变得抗凋亡，这提高了Fas缺失是肿瘤逃逸机制的一部分的可能性。然而，在人类癌症中很少看到Fas的完全丢失，许多癌细胞可能表达大量Fas，并且对Fas介导的体外凋亡高度敏感。此外，癌症患者经常有Fas生理配体FasL水平升高。这些数据提出了一种有趣的可能性，即Fas可能实际上通过其非凋亡活性促进肿瘤的生长。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的组成活性和FasL的表达，以获得最佳的生长和存活。在卵巢癌和肝癌小鼠模型中，Fas的缺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，我们提出了三个特定的研究目标：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是一种普遍的促瘤受体，其基础活性涉及JNK1诱导AP-1驱动的增殖，该活性对癌细胞存活至关重要。专项目标2：探索Fas与能量代谢之间的联系。假设：肿瘤细胞生长需要Fas和FasL调节能量代谢。特异性目的3：建立阻断FasL活性治疗癌症的临床前模型。假设：抑制FasL而不是激活FasL可用于治疗卵巢癌和肝癌。这一建议的结果将有助于描述Fas作为肿瘤启动子的新活动，并有望导致临床相关和治疗癌症的新方法。

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.