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

描述(申请人提供)：卵巢癌是女性癌症死亡的第五大原因，因为这种致命的潜伏性疾病通常是无症状的，直到恶性肿瘤蔓延到卵巢以外。虽然确切的病因尚不清楚，但越来越多的证据表明，卵巢癌是一种源于炎症性疾病的炎症相关癌症。与正常卵巢上皮细胞相比，卵巢癌细胞高表达肿瘤坏死因子-1，作为直接或间接控制趋化因子网络的主要促炎细胞因子。生长调节癌基因(CXCL1)在卵巢癌细胞、卵巢癌患者的血浆和腹水中均显著升高。我们最近的研究结果表明，CXCL1、CXCL2和CXCL8是主要的炎症驱动的趋化因子，主要由卵巢癌细胞在炎症反应中产生并大量产生。在其他系统中，CXCL1与其特异性受体CXCR2结合，发挥细胞增殖、侵袭、肿瘤形成和血管生成等功能，这可能在卵巢癌的发病机制中起关键作用。这些事实支持炎症驱动的趋化因子通过炎性肿瘤微环境促进卵巢癌，导致大量腹水和广泛的腹膜扩散，如晚期卵巢癌所描述的那样，继而导致高死亡率。特别是，高级别恶性卵巢癌中经常发生P53失活和EGFR/Akt过表达等基因修饰。基因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制。然而，炎症驱动的趋化因子在卵巢癌发病机制中的作用机制仍然知之甚少。这项研究的长期目标是确定趋化因子网络在卵巢癌发生中的具体作用。靶向炎症驱动的趋化因子将有助于更好地了解卵巢癌的发病机制，并为趋化因子作为生物标志物的潜在用途以及使用特异性趋化因子受体抑制剂和抗炎药预防和治疗卵巢癌提供重要的未来应用。通过阻断炎症驱动的趋化因子防止腹膜扩散和改善腹水，可以改善卵巢癌和其他与炎症相关的肿瘤患者的护理和总体存活率。 公共卫生相关性：卵巢癌通常是在癌症扩散到卵巢以外并导致女性生殖系统所有癌症中死亡率最高的晚期被诊断出来的。虽然确切的病因尚不清楚，但越来越多的证据表明，炎症在卵巢癌的发展、生长和进展中起着重要作用。该项目旨在明确炎症驱动的趋化因子在卵巢癌发病机制中的作用，将为未来的长期生存提供坚实的基础，降低卵巢癌的风险，并有助于设想急需的卵巢癌和其他与炎症相关的肿瘤的新疗法。

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.