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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘