The role of Fas as tumor promoter

描述（由申请人提供）：Fas（也称为CD 95和APO-1）是一种原型死亡受体，主要通过诱导细胞凋亡在免疫系统中调节组织稳态。在癌症进展过程中，Fas经常下调，或细胞呈现凋亡抗性，提高了Fas丢失是肿瘤逃避机制的一部分的可能性。然而，在人类癌症中很少看到Fas的完全丧失，并且许多癌细胞可以表达大量Fas，并且对Fas介导的体外凋亡高度敏感。此外，癌症患者经常具有升高水平的Fas、FasL的生理配体。这些数据提出了一个有趣的可能性，Fas可能实际上通过其非凋亡活性促进肿瘤的生长。我们最近的数据已经证实，一般来说，癌细胞，不管他们的Fas凋亡敏感性，依赖于Fas的组成型活性和表达的FasL的最佳生长和生存。一致的是，在卵巢癌和肝癌的小鼠模型中Fas的丢失防止或减少癌症形成，并且癌细胞中FasL的消除导致它们死亡。基于这些数据，我们提出了三个具体目标的研究：具体目标1：确定Fas/FasL对癌细胞生长和存活的作用。假设：Fas是通过涉及JNK 1诱导的AP-1驱动的增殖的基础活性的一般肿瘤促进受体，并且该活性对于癌细胞存活是必需的。具体目标2：探讨Fas与能量代谢的关系。假说：Fas和FasL调节能量代谢是肿瘤细胞生长所必需的。具体目标3：建立通过阻断FasL活性治疗癌症的临床前模型。假设：抑制FasL而不是激活Fas可用于治疗卵巢癌和肝癌。该提案的结果将有助于描述Fas作为肿瘤促进剂的新活性，并有望导致临床相关的新方法来治疗癌症。 公共卫生相关性：凋亡诱导的Fas及其配体FasL最近被认为介导组织和肿瘤细胞中的非凋亡信号。特别是在卵巢癌和肝癌的背景下，已经清楚的是，这些活动有助于癌症的形成和生长。在这项提案中，我们将表征这些新的活动，这应该是高度相关的癌症患者的治疗耐药性，并建立临床前小鼠模型，使用可溶性Fas受体阻断Fas的这些致瘤活性。

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.