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

项目总结/摘要 卵巢癌是女性癌症死亡的第五大原因， 致命的隐匿性疾病通常无症状，直到恶性肿瘤已经达到 除了卵巢。虽然确切的病因尚不清楚， 有证据表明卵巢癌是一种炎症相关的癌症， 炎症性疾病。与正常卵巢上皮细胞相比， 癌细胞高度表达肿瘤坏死因子（TNF）作为主要的促炎因子， 直接或间接控制趋化因子网络的细胞因子。生长调节 癌基因CXCL 1在卵巢癌细胞中显著增加， 卵巢癌患者的血浆和腹水。我们最近的研究表明 CXCL 1、2和8是主要的炎症驱动趋化因子， 卵巢癌细胞对炎症的反应。在其他系统中， CXCL 1结合其特异性受体（CXCR 2）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，这可能是至关重要的， 卵巢癌的发病机制。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播散，如 其次是晚期卵巢癌的高死亡率。特别是，遗传 p53失活和EGFR/Akt过表达等修饰在高血压患者中很常见， 恶性卵巢癌的治疗基因的改变增强了炎症- 趋化因子，可能加剧卵巢癌的发病机制。然而，在这方面， 炎症驱动的趋化因子的机制有助于 对卵巢癌的认识仍然很少。这项研究的长期目标是 确定趋化因子网络对卵巢癌发生的具体贡献。 靶向炎症驱动的趋化因子将导致更好地理解 卵巢癌的发病机制，并提供重要的未来应用， 趋化因子作为生物标志物的潜在用途和特异性趋化因子受体的用途 抑制剂和抗炎剂在预防和治疗卵巢癌中的应用 癌阻断法预防腹膜播散改善腹水 炎症驱动的趋化因子改善患者护理和女性的总体生存率 卵巢癌和其他与炎症有关的肿瘤。

Project Summary/Abstract 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-¿ (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.