Ovarian Cancer Initiating Cells: Metabolic Characterization

卵巢癌起始细胞：代谢特征

• 批准号: 8401323
• 负责人: Susan Kay Murphy
• 金额: $ 7.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401323
• 关键词: Address; Biological; Cancer cell line; Carcinoma; Cell surface; Cells; Cessation of life; Characteristics; Clear Cell; Complex; Data; Diagnosis; Disease; Disease remission; Epithelial ovarian cancer; Exhibits; Flow Cytometry; Foundations; Gene Expression; Genes; Growth; Gynecologic; Hand; Hypoxia Inducible Factor; In Vitro; Life Expectancy; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolic; Metabolic Pathway; Metabolism; Noscapine; Operative Surgical Procedures; Outcome Study; Ovarian; Oxygen; PTPRC gene; Pathway interactions; Phenotype; Population; Positioning Attribute; Protein Analysis; Public Health; Recurrence; Recurrent disease; Relapse; Reporting; Research; Residual Cancers; Resistance; Response Elements; Role; Salvage Therapy; Small Interfering RNA; Specimen; Staging; Stem cells; Technology; Therapeutic; Woman; Work; aldehyde dehydrogenases; base; cancer cell; chemotherapy; drug development; established cell line; hypoxia inducible factor 1; improved; inhibitor/antagonist; innovation; mortality; neoplastic cell; novel therapeutics; premature; prevent; response; self-renewal; therapeutic target; transcription factor; tumor

DESCRIPTION (provided by applicant): Epithelial ovarian cancer is the most lethal gynecologic malignancy. Although response to first line chemotherapy usually leads to complete remission, most cases relapse and then are chemoresistant, leading to premature death. We previously reported that CD133+ cells exhibit characteristics of cancer initiating cells (CICs) including the ability to undergo asymmetric division; other groups have since confirmed our findings and have improved the ability to isolate ovarian CICs by using both CD133 and ALDH cell surface markers. CICs comprise a small proportion of cells within a tumor, are able to survive chemotherapy and importantly, are thought to cause disease recurrence, sometimes years later, in part due to their ability to slow metabolism and enter quiescence. Therefore, identifying specific exploitable targets that distinguish these cells and thus increase their vulnerability is a top priority if we hope to extend life expectancy of women with this disease. Analysis of our gene expression microarray data showed that expression of genes containing Hypoxia inducible factor (HIF) response elements was enriched in CD133+ versus CD133- ovarian cancer cell populations (FDR q=0.078). HIF1¿ functions as part of a key transcription factor complex regulating metabolic pathways and processes in response to oxygen levels, with low oxygen levels tending to inhibit differentiation. Therefore, we hypothesize that CICs exhibit distinct metabolic pathway differences as compared to non-CIC tumor cells and that targeting of CICs based on these differences will alter the ability of CICs to undergo self-renewal. Our long-term objective is to develop novel therapeutic strategies based on metabolic differences to eradicate CIC populations prior to disease recurrence. Aim 1 of this proposal is to generate metabolic profiles of CIC cells versus non-CIC ovarian cancer cells for over 2,300 known metabolites and 5,200 unnamed compounds and then determine how CICs differ from non-CICs by identifying the specific cellular pathways and components involved. We will then validate the differential abundance of metabolites and determine if the proportion of CICs can be altered by targeting the specific pathways identified using siRNA technology or relevant therapeutic inhibitors. In Aim 2, we will determine if the CIC / non-CIC ratio in ovarian cancer cells can be altered by modulating HIF1 pathway activity. Successful completion of these aims will greatly increase understanding of how CICs are able to survive chemotherapy and enter into prolonged remission - by altering their metabolism - to later emerge in chemoresistant form during relapse. Identifying relevant pathways and biological targets that elicit this ovarian CIC phenotype offers an unprecedented opportunity to target the cell population ultimately responsible for the high mortality of this disease. PUBLIC HEALTH RELEVANCE: Statement of Relevance to Public Health Epithelial ovarian cancer is a disease that is most commonly diagnosed at an advanced stage. This proposal seeks to elucidate comprehensive metabolic profiles of the small subset of ovarian cancer cells that are responsible for disease recurrence, and identify specific exploitable therapeutic targets based on these profiles that will allow targeting of these cells and help prevent recurrence of the primary cancer. Successful completion of this work will offer an unprecedented opportunity to find specific vulnerabilities that will eventually allow for eradication of the cells ultimately responsible for the high mortality associated with ovarian cancer.

描述（由申请人提供）：上皮性卵巢癌是最致命的妇科恶性肿瘤。虽然对一线化疗的反应通常导致完全缓解，但大多数病例复发，然后耐药，导致过早死亡。我们以前报道过，CD 133+细胞表现出癌症起始细胞（CIC）的特征，包括进行不对称分裂的能力;其他研究组已经证实了我们的发现，并通过使用CD 133和ALDH细胞表面标志物提高了分离卵巢CIC的能力。CIC包括肿瘤内的一小部分细胞，能够在化疗中存活，重要的是，被认为会导致疾病复发，有时几年后，部分原因是它们能够减缓代谢并进入静止状态。因此，如果我们希望延长患有这种疾病的女性的预期寿命，那么确定区分这些细胞并从而增加其脆弱性的特定可利用目标是首要任务。我们的基因表达微阵列数据的分析表明，表达的基因含有缺氧诱导因子（HIF）的反应元件富集在CD 133+与CD 133-卵巢癌细胞群体（FDR q=0.078）。HIF 1？作为关键转录因子复合物的一部分，响应氧水平调节代谢途径和过程，低氧水平倾向于抑制分化。因此，我们假设CIC与非CIC肿瘤细胞相比表现出明显的代谢途径差异，并且基于这些差异靶向CIC将改变CIC进行自我更新的能力。我们的长期目标是根据代谢差异开发新的治疗策略，在疾病复发前根除CIC人群。该提案的目的1是生成CIC细胞与非CIC卵巢癌细胞的2，300多种已知代谢物和5，200种未命名化合物的代谢谱，然后通过识别所涉及的特定细胞途径和组分来确定CIC与非CIC的差异。然后，我们将验证代谢物的差异丰度，并确定CIC的比例是否可以通过靶向使用siRNA技术或相关治疗抑制剂鉴定的特定途径来改变。在目标2中，我们将确定是否可以通过调节HIF 1通路活性来改变卵巢癌细胞中的CIC /非CIC比率。成功完成这些目标将大大增加对CIC如何能够在化疗中存活并进入长期缓解的理解-通过改变它们的代谢-后来在复发期间以耐药形式出现。鉴定引起这种卵巢CIC表型的相关途径和生物靶点提供了前所未有的机会，以靶向最终导致这种疾病高死亡率的细胞群。 公共卫生相关性：卵巢癌是一种常见的恶性肿瘤，是一种常见的恶性肿瘤。该提案旨在阐明负责疾病复发的卵巢癌细胞的小子集的综合代谢谱，并基于这些谱鉴定将允许靶向这些细胞并帮助预防卵巢癌复发的特定可利用的治疗靶点。 原发性癌症这项工作的成功完成将提供一个前所未有的机会，找到特定的脆弱性，最终将允许根除最终导致卵巢癌高死亡率的细胞。