Reactive Oxygen Species-Induced CXCL8 in Ovarian Cancer

活性氧诱导的 CXCL8 在卵巢癌中的作用

基本信息

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
项目类别：
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

项目摘要

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，增加的活性氧（ROS）水平在高级浆液卵巢癌（HGSOC）的生物学中起重要作用，但是尚未阐明ROS参与的确切机制。我们的初步发现表明，较高的ROS诱导的CXCL8表达和GSK-3B在卵巢癌细胞系和原发性人肿瘤组织中的失活。 HGSOC组织中CXCL8的表达增加以及同源受体CXCR1/2的升高与不利的临床过程有关。我们假设ROS调节CXCL8表达以介导肿瘤生长和血管生成，其中CXCL8作为促进血管生成的旁分泌因子起重要作用，并且有可能作为增加增殖的自分泌生长因子。为了检验这一假设，我们建议执行以下三个目标。在AIM 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磷酸化在肿瘤细胞中诱导CXCL8表达的作用和机制，从而导致其肿瘤生长的阴性调节失活。肿瘤细胞中ROS，CXCL8和活性GSK-3B的表达水平的调节将通过表达过氧化氢酶，CXCL8敲低或过表达获得，以及组成型活性或显性阴性GSK-3B的表达。在AIM 2中，我们将使用人源化的嵌合肿瘤模型来确定CXCL8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，其中人类内皮细胞（EC）和人类癌细胞通过VIVO中的多孔PLGA Sponges共同植入。将研究对EC和肿瘤细胞中CXCR1和CXCR2敲低的肿瘤生长和血管生成的影响（分别或同时）。在AIM 3中，我们将确定ROS，CXCL8和GSK-3B磷酸化/灭活或/以及具有肿瘤阶段的活性以及HGSOC患者在一组原发性人类肿瘤组织（带有临床注释）中的HGSOC患者的水平和相关性。这项研究将为通过CXCL8调节卵巢肿瘤生物学的新分子机制提供重要的见解，并可能揭示ROS/GSK-3B/CXCL8信号传导途径的未来潜力，以作为HGSOC的新型治疗靶标。