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

促炎性网膜微环境在卵巢癌进展中的作用

• 批准号: 10443384
• 负责人: Chi Lam Au Yeung
• 金额: $ 44.04万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-03 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443384
• 关键词: Adipocytes; Adipose tissue; Anti-Inflammatory Agents; Attenuated; Binding; Blood Vessels; Body Weight decreased; CD8-Positive T-Lymphocytes; CXCL12 gene; Cancer Patient; Cancer Survivor; Cell Density; Cell surface; Cells; Chemopreventive Agent; Coupling; Cytotoxic T-Lymphocytes; Development; Endothelial Cells; Event; Genes; Glucose; Glycosaminoglycans; Immune; Immune response; Immunologic Surveillance; Immunomodulators; Immunosuppression; Infiltration; Inflammation; Inflammatory; Interstitial Collagenase; Intra-abdominal; Lactoferrin; Lymphocyte; Malignant neoplasm of ovary; Mediating; Mesothelial Cell; Metabolic; Mus; Neoplasm Metastasis; Nutritional; Omentum; Ovary; Paclitaxel; Pathogenesis; Patients; Peritoneal; Play; Prevention strategy; Proteins; Proteomics; Regulatory T-Lymphocyte; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Serous; Serum; Signal Transduction; Site; Stromal Cells; Survival Rate; Survivors; T-Cell Activation; TNF gene; Testing; Therapeutic Agents; Time; Tissues; Toxic effect; Traction; Tumor Angiogenesis; Tumor Tissue; Tumor-infiltrating immune cells; Up-Regulation; Visceral; abdominal fat; adipokines; angiogenesis; base; cancer cell; cancer invasiveness; cancer recurrence; cancer therapy; cell growth; cell motility; cell type; chemokine; cytokine; effector T cell; exercise program; improved; innovation; mRNA Expression; malignant phenotype; mass spectrometric imaging; mouse model; novel; ovarian neoplasm; pharmacokinetics and pharmacodynamics; pressure; prevent; receptor; secretory protein; trafficking; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; uptake

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.

项目摘要/摘要 高级别浆液性卵巢癌(HGSC)优先于大网膜转移，这是一个很好的- 腹膜间皮细胞覆盖的腹膜血管化皱折和腹内脂肪的主要部位 积累。据报道，HGSC和基质细胞衍生的促炎细胞因子下调 奥米替丁(ITLN1)--一种促进间皮细胞源性脂肪细胞增殖和侵袭潜能的新因子 大网膜微环境中癌细胞的数量。Oentin已被证明可以抑制卵巢癌的侵袭 通过抑制癌细胞中MMP1的表达和细胞牵引力来实现潜能和细胞生长 在卵巢癌细胞和邻近脂肪细胞之间诱导局部快速代谢偶联。再说了， HGSC患者术前血清OMENTIN水平较高与生存时间较长相关。 此外，奥米替丁治疗的小鼠激活的CD8+T细胞密度比 未经处理的对照组。这些发现表明，脂肪细胞在调节这种抑制中起着重要作用。 奥米替丁对卵巢癌细胞恶性表型及免疫微环境的影响。 因此，我们将重点放在成熟脂肪细胞中可被奥米替丁上调的分泌蛋白上。最近 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)是奥米替丁上调脂肪细胞表达的最高基因。以往的研究表明，TSG-6 抑制炎症过程中免疫细胞的渗透。它还可以与特定的趋化因子结合，如CXCL12 并阻止它们与富含糖胺聚糖(GAG)的肿瘤间质和内皮细胞表面结合，提示 TSG-6介导的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，我们假设奥米替丁使促炎大网膜正常化。 卵巢癌的微环境通过上调脂肪细胞中的抗炎TSG-6，它与 由癌细胞和各种类型的间质细胞分泌的促炎细胞因子，可以减弱 免疫抑制肿瘤微环境，防止大网膜转移，抑制肿瘤进展， 从而提高患者的存活率。为了检验这一假设，首先，我们建议确定 奥米替丁在规范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omentin重新编程免疫的机制。 并抑制卵巢癌细胞的侵袭潜能。第三，我们 建议确定奥米替丁单独或与紫杉醇联合应用于卵巢的疗效 癌症治疗，并确定奥美汀的药代动力学/药效学和毒性使用不同的 老鼠模型。我们的研究将使我们能够描述omentin在HGSC中的免疫调节作用 并进一步开发奥米替丁作为化学预防和治疗药物治疗食道癌。 HGSC以提高患者存活率。