Roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer

炎症驱动的趋化因子在卵巢癌发病机制中的作用

基本信息

批准号：
8127815
负责人：
DEOK-SOO SON
金额：
$ 35.9万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8127815
关键词：
1-Phosphatidylinositol 3-Kinase Anti-Inflammatory Agents Anti-inflammatory Ascites Aspirin Attenuated Automobile Driving Basic Science Binding Bioinformatics Biological Markers Biomedical Research CXCL1 gene Cancer Etiology Cell Proliferation Cessation of life Chronic Clinical Collaborations Core Facility Data Development Diagnosis Disease EGF gene Endocrine Environment Epidermal Growth Factor Receptor Epithelial Epithelial Cells Equipment Etiology Event Exposure to Flow Cytometry Foundations Funding Funding Mechanisms Future Genes Genetic Goals Growth Growth and Development function Gynecologic Oncology Health IL8RB gene In Vitro Infiltration Inflammation Inflammatory Interleukin-8B Receptor Intraperitoneal Injections Knockout Mice Laboratories Lead Letters Leukocytes Link Mainstreaming Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Manuscripts Measures Methods Minority Mitogen-Activated Protein Kinases Modification Molecular Molecular Biology Molecular Target Morbidity - disease rate Mus Mutation Nuclear Oncogenes Ovarian Ovary Paper Pathogenesis Pathway interactions Patient Care Patients Peer Review Peritoneal Pharmaceutical Preparations Plasma Postdoctoral Fellow Prevention Probability Process Proto-Oncogene Proteins c-akt Publications Publishing Receptor Activation Receptor Signaling Research Research Personnel Resources Role Scientist Serine Signal Transduction Son Staging Stimulus Students System Techniques Therapeutic Threonine Time Training Transfection Tumor Burden Tumor Cell Invasion Tumor Necrosis Factor-alpha Tumor Suppressor Genes Universities Vascular Endothelial Growth Factors Veterinarians Western Blotting Woman Women&apos s Health Work Yang angiogenesis animal care cancer cell cancer risk carcinogenesis cell growth chemokine chemokine receptor cytokine female reproductive system improved in vitro Assay in vivo inhibitor/antagonist medical schools member migration mortality novel novel therapeutics overexpression planetary Atmosphere prevent programs research study response restoration square foot tissue culture tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth leading cause of cancer deaths among women because this deadly insidious disease is typically asymptomatic until the malignancy has reached beyond the ovaries. Although the precise etiology remains unknown, the increasing evidence indicates ovarian cancer is one of inflammation-associated cancers derived from inflammatory diseases. Compared with normal ovarian epithelial cells, ovarian cancer cells expressed highly tumor necrosis factor-1 (TNF) as a main proinflammatory cytokine that controls directly or indirectly chemokine networks. Growth-regulated oncogene (CXCL1) was significantly increased in ovarian cancer cells, and in the plasma and ascites of patients with ovarian cancer. Our recent studies have resulted that CXCL1, 2 and 8 are main inflammation-driven chemokines produced primarily and abundantly from ovarian cancer cells in response to inflammation. In other system, CXCL1 binds its specific receptor (CXCR2) and exert several functional roles such as cell proliferation, invasion, tumor formation and angiogenesis, which may be critical in the pathogenesis of ovarian cancer. These facts support that inflammation-driven chemokines promote ovarian cancer through inflammatory tumor microenvironments, which lead to massive ascites and widespread peritoneal dissemination as described in advanced ovarian cancer followed by the high mortality rate. In particular, genetic modifications such as p53 inactivity and EGFR/Akt overexpression are frequent in high- grade malignant ovarian cancer. The genetic modifications potentiate inflammation- driven chemokines, probably exacerbating the pathogenesis of ovarian cancer. However, the mechanisms inflammation-driven chemokines contribute to the pathogenesis of ovarian cancer are still poorly understood. The long-range goal of this research is to determine the specific contribution of chemokine networks to ovarian carcinogenesis. Targeting inflammation-driven chemokines will lead to a better understanding of the pathogenesis of ovarian cancer and provide important future applications for the potential use of chemokines as a biomarker and for use of specific chemokine receptor inhibitors and anti-inflammatory agents in the prevention and treatment of ovarian cancer. Preventing peritoneal dissemination and ameliorating ascites through blockage of inflammation-driven chemokines improve patient care and overall survival of women with ovarian cancer and other tumors related to inflammation. PUBLIC HEALTH RELEVANCE: Ovarian cancer is often diagnosed at an advanced stage after the cancer has spread beyond the ovary and results to the highest mortality of all cancers of the female reproductive system. Although the precise etiology remains unknown, the increasing evidence has emerged to indicate an impact of inflammation in the development, growth and progression of ovarian cancer. This project to define roles of inflammation-driven chemokines in the pathogenesis of ovarian cancer will provide a firm foundation for future long-term survival reducing ovarian cancer risks and help to envisage much- needed novel therapies for ovarian cancer and other tumors related to inflammation.

描述（由申请人提供）：卵巢癌是女性癌症死亡的第五个主要原因，因为这种致命的阴险疾病通常是无症状的，直到恶性肿瘤超出了卵巢。尽管确切的病因尚不清楚，但越来越多的证据表明卵巢癌是炎症相关的癌症之一，这些癌症来自炎症性疾病。与正常的卵巢上皮细胞相比，卵巢癌细胞表达了高度肿瘤坏死因子1（TNF）作为直接或间接趋化趋化因子网络的主要促炎细胞因子。在卵巢癌细胞以及卵巢癌患者的血浆和腹水中，生长调节的癌基因（CXCL1）显着增加。我们最近的研究导致CXCL1、2和8是主要炎症趋化趋化因子，主要是由卵巢癌细胞产生的，响应于炎症。在其他系统中，CXCL1结合其特异性受体（CXCR2），并发挥多种功能作用，例如细胞增殖，侵袭，肿瘤形成和血管生成，这对于卵巢癌的发病机理可能至关重要。这些事实支持通过炎症肿瘤微环境促进炎症趋势趋化因子促进卵巢癌，从而导致大量的腹水和广泛的腹膜传播，如晚期卵巢癌中所述，随后是高死亡率。特别是，在高级恶性卵巢癌中，遗传修饰（例如p53不活跃和EGFR/AKT）经常进行。遗传修饰增强了炎症驱动的趋化因子，可能加剧了卵巢癌的发病机理。然而，炎症趋化趋化因子的机制导致卵巢癌的发病机理的理解仍然很少。这项研究的远程目标是确定趋化因子网络对卵巢癌发生的特定贡献。靶向炎症驱动的趋化因子将更好地了解卵巢癌的发病机理，并为将趋化因子作为生物标志物的潜在使用以及使用特定的趋化因子受体抑制剂和抗炎药在预防和治疗卵巢癌中的使用提供了重要的未来应用。通过阻塞炎症趋化趋化因子可以改善患者护理和卵巢癌妇女的总体存活，从而防止腹膜传播和改善腹水，以及与炎症有关的其他肿瘤。公共卫生相关性：癌症癌症经常在癌症扩散后的晚期阶段被诊断出来，结果是女性生殖系统所有癌症的最高死亡率。尽管确切的病因尚不清楚，但越来越多的证据表明炎症对卵巢癌的发育，生长和发展产生了影响。该项目旨在定义炎症趋化趋化因子在卵巢癌发病机理中的作用，将为未来的长期生存降低卵巢癌的风险提供坚定的基础，并有助于设想急需的卵巢癌和其他与炎症有关的新型疗法。