Role of autophagy in tumor cell death

自噬在肿瘤细胞死亡中的作用

• 批准号: 8220991
• 负责人: Andrew M Thorburn
• 金额: $ 40.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220991
• 关键词: Adjuvant; Affect; Aftercare; Antineoplastic Agents; Apoptosis; Autophagocytosis; Behavior; Breast Cancer Cell; Breast Cancer Treatment; Catabolic Process; Cell Death; Cell physiology; Cells; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Confusion; Data; Dendritic Cells; Development; Effectiveness; Genetic; HMGB1 gene; Immune; Immune response; Immune system; Lead; Malignant Neoplasms; Metastatic Neoplasm to the Breast; Methods; Mitochondria; Modeling; Mus; Neoadjuvant Therapy; Nuclear Protein; Nutrient; Outcome; Patients; Pharmaceutical Preparations; Process; Proteins; Recycling; Reporting; Role; Stress; Testing; Toll-like receptors; Treatment Effectiveness; Uncertainty; Vesicle; Work; anticancer research; base; cancer cell; cancer therapy; cell killing; cellular imaging; chemotherapy; deprivation; imaging modality; improved; in vivo; inhibition of autophagy; inhibitor/antagonist; insight; interest; killings; neoplastic cell; novel; public health relevance; research study; response; success; therapy development; toll-like receptor 4; treatment effect; tumor; tumorigenic

DESCRIPTION (provided by applicant): There is great interest in manipulating autophagy to improve cancer treatment but considerable confusion about how to do so. For example, it has become clear in the last few years that many anti-cancer treatments induce autophagy in tumor cells, however, because this autophagy has been reported to both protect and kill tumor cells, even such a basic question as whether we should try to increase or decrease autophagy during cancer treatment is unclear. Despite this uncertainty, clinical trials are being developed that combine autophagy inhibitors with other drugs while other patients are treated with drugs that induce autophagy but without any consideration for how this autophagy affects the outcome. Thus a major need in cancer research is to better understand the roles of autophagy in tumor cell death so that we can decide how best to manipulate autophagy in people with cancer. We recently discovered a previously unrecognized function for autophagy: autophagy controls the selective release of the nuclear protein HMGB1 from dying tumor cells. HMGB1 release from dying tumor cells is known to lead to a beneficial tumor-specific immune response through activation of Toll-like Receptors on dendritic cells but may also induce non-beneficial pro-tumorigenic activities. Therefore, our recent findings open up an entirely new issue that needs to be dealt with as we consider how to manipulate autophagy in people. We hypothesize that it is not just the efficiency of tumor cell killing that is important but that the characteristics of the dying tumor cells, exemplified by selective release of HMGB1, also determines the overall success of treatment. And, we propose that autophagy controls both these processes. To test this hypothesis we will use a well-characterized model of metastatic breast cancer to complete the following aims. Aim 1. Determine how autophagy controls the efficiency and characteristics of tumor cell killing by anti-cancer treatments. This aim will test the hypothesis that autophagy regulates both the efficiency of tumor cell killing and the release of HMGB1 from dying cells but does so differently for different kinds of anti-cancer treatments. Aim 2. Determine which aspects of the autophagic process are required for the different responses during tumor cell death. Autophagy is a dynamic process that involves multiple steps; in this aim, we test the hypothesis that different steps in the process are required for the different functions of autophagy and we use novel single cell imaging methods to determine how autophagy regulates the core apoptosis machinery. Aim 3. Determine how manipulation of autophagy alters the long-term efficacy of cancer treatment in vivo. In this aim, we test the hypothesis that autophagy manipulation can determine the long term effectiveness of breast cancer treatment using a model of adjuvant and neoadjuvant chemotherapy and we will determine which functions of autophagy are important for controlling the response to therapy. These studies will give us new insights into the role of autophagy during tumor cell death and should provide a rationale for developing autophagy manipulation strategies to improve the effectiveness of cancer treatment. PUBLIC HEALTH RELEVANCE: In the last few years it has become clear that a hitherto understudied cellular process called autophagy is an important regulator of cancer development and treatment. Although it is widely believed that autophagy is important during tumor cell death (e.g. after treatment with anti-cancer drugs), the precise roles for autophagy are unclear and it has been reported that autophagy may both protect tumor cells and cause their death under different circumstances. Our lack of understanding of what autophagy does during tumor cell death limits our ability to manipulate autophagy in order to improve cancer treatment. We recently discovered a new function for autophagy during tumor cell killing- autophagy regulates the release of a protein that controls the immune system. We propose that this function along with autophagy's ability to control the amount of tumor cell killing will together determine whether efforts to kill cancer cells are effective or not. The work proposed here will test these ideas and determine how autophagy controls the amount and characteristics of tumor cell death and should provide a framework to attempt to manipulate autophagy in people who are being treated for cancer in order to improve the benefits of the treatment.

描述（由申请人提供）：人们对操纵自噬来改善癌症治疗非常感兴趣，但对如何做到这一点却相当困惑。例如，在过去的几年里，我们已经清楚，许多抗癌治疗诱导肿瘤细胞的自噬，然而，由于这种自噬已经被报道为既保护又杀死肿瘤细胞，甚至像我们在癌症治疗过程中是否应该尝试增加或减少自噬这样的基本问题也不清楚。尽管存在这种不确定性，临床试验正在开展，将自噬抑制剂与其他药物联合使用，而其他患者使用诱导自噬的药物治疗，但不考虑这种自噬如何影响结果。因此，癌症研究的一个主要需求是更好地了解自噬在肿瘤细胞死亡中的作用，以便我们能够决定如何最好地操纵癌症患者的自噬。我们最近发现了一个以前未被认识到的自噬功能：自噬控制着垂死肿瘤细胞中核蛋白HMGB1的选择性释放。已知从垂死肿瘤细胞释放HMGB1可通过激活树突状细胞上的toll样受体导致有益的肿瘤特异性免疫反应，但也可能诱导非有益的促肿瘤活性。因此，我们最近的发现开辟了一个全新的问题，当我们考虑如何操纵人体自噬时，需要处理这个问题。我们推测，重要的不仅是肿瘤细胞杀伤的效率，还有垂死肿瘤细胞的特征，例如HMGB1的选择性释放，也决定了治疗的总体成功。我们认为自噬控制着这两个过程。为了验证这一假设，我们将使用一个特征良好的转移性乳腺癌模型来完成以下目标。目的1。确定自噬如何控制抗癌治疗杀死肿瘤细胞的效率和特征。这一目标将验证自噬调节肿瘤细胞杀伤效率和垂死细胞HMGB1释放的假设，但对不同种类的抗癌治疗有不同的作用。目标2。确定自噬过程的哪些方面是肿瘤细胞死亡过程中不同反应所必需的。自噬是一个涉及多个步骤的动态过程；在此目的中，我们验证了自噬不同功能需要不同过程步骤的假设，并使用新的单细胞成像方法来确定自噬如何调节核心细胞凋亡机制。目标3。确定自噬操作如何改变体内癌症治疗的长期疗效。在这个目的中，我们使用辅助和新辅助化疗模型来验证自噬操作可以决定乳腺癌治疗的长期有效性的假设，我们将确定自噬的哪些功能对控制治疗反应是重要的。这些研究将使我们对自噬在肿瘤细胞死亡中的作用有新的认识，并为开发自噬操作策略以提高癌症治疗的有效性提供理论依据。