Reactive Oxygen Species-Induced CXCL8 in Ovarian Cancer

活性氧诱导的 CXCL8 在卵巢癌中的作用

• 批准号: 8692266
• 负责人: BingHua Jiang
• 金额: $ 20.25万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692266
• 关键词: Adverse reactions; African American; American Cancer Society; American Society of Clinical Oncology; Angiogenic Factor; Biological Markers; Biological Models; Biology; CXC Chemokines; Cancer Patient; Cancer cell line; Carcinoma; Caucasians; Caucasoid Race; Cell Line; Clinical; Clinical Trials; Combination Drug Therapy; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Distant; Dominant-Negative Mutation; Endothelial Cells; Enterochromaffin Cells; Excision; Functional disorder; Future; Growth Factor; HIF1A gene; Healthcare; Human; IL8 gene; IL8RA gene; IL8RB gene; Implant; Interleukin 8A Receptor; Interleukin-8; Islets of Langerhans; Kidney; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Neoplasms in Vascular Tissue; Operative Surgical Procedures; Organ Transplantation; Ovarian; Ovarian Carcinoma; Ovarian Serous Adenocarcinoma; Patients; Phosphorylation; Platinum; Play; Porifera; Progression-Free Survivals; Proteins; Reactive Oxygen Species; Refractory; Regulation; Role; Sampling; Signal Pathway; Signal Transduction; Staging; Stimulus; Survival Rate; Taxane Compound; Testing; Therapeutic; Tissues; Tumor Angiogenesis; Tumor Biology; Tumor Tissue; Tumor stage; Vascular Endothelial Growth Factors; Woman; Xenograft Model; Xenograft procedure; abstracting; advanced disease; angiogenesis; autocrine; bevacizumab; cancer cell; catalase; chemotherapy; clinically relevant; cohort; density; in vivo; inhibitor/antagonist; insight; mortality; neoplastic cell; new therapeutic target; novel; ovarian neoplasm; paracrine; public health relevance; receptor; research study; response; taxane; trend; tumor; tumor growth

DESCRIPTION (provided by applicant): Recent studies have shown that increased levels of reactive oxygen species (ROS) play an important role in the biology of high grade serous ovarian carcinoma (HGSOC), but the precise mechanisms for the involvement of ROS have not yet been elucidated. Our preliminary findings revealed that higher levels of ROS induced expression of CXCL8 and inactivation of GSK-3b in ovarian cancer cell lines and primary human tumor tissues. Increased expression of CXCL8, as well as elevated levels of the cognate receptors, CXCR1/2, in HGSOC tissues have been associated with an unfavorable clinical course. We hypothesize that ROS regulate CXCL8 expression to mediate tumor growth and angiogenesis in which CXCL8 plays a significant role as a paracrine factor for promoting angiogenesis, and, potentially as an autocrine growth factor for increasing proliferation. To test this hypothesis, we propose to perform the following three aims. In Aim 1, we will use a mouse orthotopic xenograft model to determine the role and mechanism by which ROS induce CXCL8 expression in tumor cells via phosphorylation of GSK-3b, resulting in inactivation of its negative regulation of tumor growth. Modulation of expression levels of ROS, CXCL8 and active GSK- 3b in tumor cells will obtained by expression of catalase, CXCL8 knockdown or over-expression, and expression of constitutively active or dominant negative GSK-3b. In Aim 2, we will determine the paracrine and autocrine effects of CXCL8 in ROS-induced tumor growth and angiogenesis using a humanized chimeric tumor model in which human endothelial cells (EC) and human cancer cells are co-implanted via porous PLGA sponges in vivo. The effect on tumor growth and angiogenesis of the knockdown of CXCR1 and CXCR2 in EC and tumor cells (separately or simultaneously) will be investigated. In Aim 3, we will determine levels and correlations of ROS, CXCL8, and GSK-3b phosphorylation/inactivation or/and activities with tumor stages and survival in patients with HGSOC in a panel of primary human tumor tissues (with clinical annotation). This study will provide important insights into a new molecular mechanism for the regulation of ovarian tumor biology via CXCL8, and may reveal the future potential for the ROS/GSK-3b/CXCL8 signaling pathway to serve as novel therapeutic target for HGSOC.

描述（由申请人提供）：最近的研究表明，活性氧（ROS）水平的增加在高级别浆液性卵巢癌（HGSOC）的生物学中起重要作用，但ROS参与的确切机制尚未阐明。我们的初步研究结果显示，较高水平的ROS诱导卵巢癌细胞系和原发性人类肿瘤组织中CXCL 8的表达和GSK-3b的失活。HGSOC组织中CXCL 8表达增加以及同源受体CXCR 1/2水平升高与不利的临床过程相关。我们假设ROS调节CXCL 8表达以介导肿瘤生长和血管生成，其中CXCL 8作为促进血管生成的旁分泌因子发挥重要作用，并且可能作为增加增殖的自分泌生长因子。为了验证这一假设，我们提出了以下三个目标。在目标1中，我们将使用小鼠原位异种移植模型来确定ROS通过GSK-3b的磷酸化诱导肿瘤细胞中CXCL 8表达的作用和机制，从而导致其对肿瘤生长的负调控失活。肿瘤细胞中ROS、CXCL 8和活性GSK- 3b的表达水平的调节将通过过氧化氢酶的表达、CXCL 8敲低或过表达以及组成型活性或显性阴性GSK-3b的表达来获得。在目标2中，我们将使用人源化嵌合肿瘤模型来确定CXCL 8在ROS诱导的肿瘤生长和血管生成中的旁分泌和自分泌作用，在所述人源化嵌合肿瘤模型中，人内皮细胞（EC）和人癌细胞通过多孔PLGA海绵在体内共植入。将研究EC和肿瘤细胞中CXCR 1和CXCR 2的敲低（分别或同时）对肿瘤生长和血管生成的影响。在目标3中，我们将确定一组原发性人类肿瘤组织中HGSOC患者的ROS、CXCL 8和GSK-3b磷酸化/失活或/和活性的水平和相关性（具有临床注释）。这项研究将为通过CXCL 8调节卵巢肿瘤生物学的新分子机制提供重要见解，并可能揭示ROS/GSK-3b/CXCL 8信号通路作为HGSOC新治疗靶点的未来潜力。