Role of the pro-inflammatory omental microenvironment in ovarian cancer progression

项目总结/摘要 高级别浆液性卵巢癌（HGSC）优先转移到网膜，这是一个很好的选择。 腹膜组织的血管化褶皱，被间皮细胞覆盖，是腹内脂肪的主要部位 积累有报道称HGSC和基质细胞源性促炎细胞因子下调 网膜素（omentin，ITLN 1）是一种新的间皮细胞源性脂肪因子，可促进间皮细胞的侵袭和增殖 癌细胞在网膜微环境中的作用。Omentin已被证明可以抑制卵巢癌的侵袭性 通过抑制癌细胞中的MMP 1表达和细胞牵引力来促进细胞生长，以及 诱导卵巢癌细胞和邻近脂肪细胞之间的局部快速代谢偶联。此外，我们认为， HGSC患者术前血清网膜素水平较高与生存时间较长相关。 此外，与对照组相比，用网膜素治疗的小鼠活化的CD 8 + T细胞密度显著增加。 未处理的对照。这些结果表明，脂肪细胞在介导抑制性细胞凋亡中起重要作用。 网膜素对卵巢癌细胞恶性表型及免疫微环境的影响。 因此，我们专注于分泌蛋白，可以上调网膜在成熟的脂肪细胞。最近的一 蛋白质组学研究表明，抗炎蛋白肿瘤坏死因子诱导基因6蛋白 TSG-6是网膜素上调的脂肪细胞基因。先前的研究表明，TSG-6 抑制炎症期间免疫细胞的浸润。它还可以结合特定的趋化因子，如CXCL 12 并阻止它们与富含糖胺聚糖（GAG）的肿瘤基质和内皮细胞表面结合，这表明 TSG-6介导阻断这些细胞因子以抑制肿瘤生长、血管生成和调节性T细胞 贩卖人口基于这些发现，我们假设网膜素使促炎性网膜正常化， 通过上调脂肪细胞中的抗炎性TSG-6，其结合到卵巢癌微环境中， 由癌细胞和各种基质细胞类型分泌的促炎细胞因子，其减弱了肿瘤细胞的增殖。 免疫抑制肿瘤微环境，预防网膜转移，抑制肿瘤进展， 从而提高患者的生存率。为了验证这一假设，首先，我们建议确定 网膜素在正常化免疫抑制微环境和预防肿瘤发展中的作用 卵巢癌其次，我们建议确定网膜素重新编程免疫系统的机制， 在卵巢肿瘤组织中的景观和抑制卵巢癌细胞的侵袭潜力。三是 建议确定网膜素单独给药或与紫杉醇联合给药在卵巢癌中的疗效， 癌症治疗，并使用各种方法确定网膜素的药代动力学/药效学和毒性。 小鼠模型。我们的研究将使我们能够阐明网膜素在HGSC中的免疫调节作用 发病机制，并进一步开发网膜素作为化学预防和治疗剂，在治疗 HGSC提高患者的生存率。

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSC) metastasizes preferentially to the omentum, which is a well- vascularized fold of peritoneal tissue covered by mesothelial cells and a major site of intra-abdominal fat accumulation. It was reported that HGSC and stromal cell-derived pro-inflammatory cytokines downregulate omentin (ITLN1), a novel mesothelial cell-derived adipokine to promote the invasive potential and proliferation of cancer cells in the omental microenvironment. Omentin has been shown to suppress ovarian cancer invasive potential and cell growth through suppressing MMP1 expression and cell traction force in cancer cells, and inducing a local rapid metabolic coupling between ovarian cancer cells and neighboring adipocytes. Besides, higher levels of pre-operative serum omentin in patients with HGSC were associated with longer survival times. In addition, mice treated with omentin had marked increase in activated CD8+ T cell density compared to the untreated control. These findings suggested that adipocytes play an important role in mediating the suppressive effect of omentin on the malignant phenotype of ovarian cancer cells, and the immune microenvironment. Therefore, we focus on secretory proteins that can be upregulated by omentin in mature adipocytes. A recent proteomic study demonstrated that an anti-inflammatory protein tumor necrosis factor-inducible gene 6 protein (TSG-6) was the top gene upregulated by omentin in adipocytes. Previous studies demonstrated that TSG-6 inhibits infiltration of immune cells during inflammation. It can also bind to specific chemokines such as CXCL12 and prevent them to bind to glycosaminoglycan (GAG)-rich tumor stroma and endothelial cell surface, suggesting that TSG-6-mediated blockade of these cytokines to suppress tumor growth, angiogenesis, and regulatory T cell trafficking. Based on these findings, we hypothesize that omentin normalizes the pro-inflammatory omental microenvironment in ovarian cancer through upregulating anti-inflammatory TSG-6 in adipocytes, which binds to pro-inflammatory cytokines secreted by cancer cells and various stromal cell types, which attenuate the immunosuppressive tumor microenvironment, prevent omental metastasis, and suppress tumor progression, and subsequently improve patients’ survival rate. To test this hypothesis, first, we propose to determine the roles of omentin in normalizing the immunosuppressive microenvironment and preventing tumor development in ovarian cancer. Second, we propose to determine the mechanisms by which omentin reprograms the immune landscape in ovarian tumor tissues and suppresses the invasive potential of ovarian cancer cell. Third, we propose to determine the efficacy of omentin administration alone or in combination with paclitaxel in ovarian cancer treatment, and determine the pharmacokinetics/pharmacodynamics and toxicity of omentin using various mouse models. Our studies will enable us to delineate the immune modulator role of omentin in HGSC pathogenesis, and to further develop omentin as a chemopreventive and therapeutic agent in the treatment of HGSC to improve patients’ survival rates.