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Pre-metastatic Omental Niche Formation in Ovarian Cancer

卵巢癌转移前网膜微环境的形成

基本信息

批准号：
10117199
负责人：
Honami Naora
金额：
$ 37.41万
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：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117199
关键词：
Adipocytes Cancer Model Cancer Patient Cause of Death Cell Death Cell Differentiation process Cells Clinical Clinical Management Communicable Diseases Consumption Cystic Fibrosis DNA Deoxyribonucleases Development Disease Enzymes Fatty acid glycerol esters Fibroblasts Genetic Models Goals Greater sac of peritoneum Growth Human Immune Implant Infection Inflammatory Internet Intestinal Obstruction Intestines Knockout Mice Malignant Neoplasms Malignant neoplasm of ovary Mesothelial Cell Metastatic Malignant Neoplasm to the Ovary Microbe Modeling Mus Neoplasm Metastasis Omentum Patients Pharmaceutical Preparations Pharmacology Protein-arginine deiminase Recombinants Risk Role Site Specimen Stomach Stromal Cells Time Tissues Tropism Visceral fat Woman Work Xenograft Model base cancer cell cancer therapy chemotherapy cost effective drug repurposing effective therapy experience extracellular implantation inhibitor/antagonist insight macrophage multidisciplinary neutrophil novel novel therapeutics ovarian neoplasm response stem tumor tumor growth tumor progression

项目摘要

Bowel obstruction is a leading cause of death in women with ovarian cancer and often stems from growth of tumors on the omentum, a fat pad that suspends from the stomach. The objective of this project is to determine the mechanisms that cause ovarian cancer cells to implant on the omentum, with the overarching goal of identifying more effective therapies for this lethal disease. Previous studies of ovarian cancer metastasis have mostly focused on investigating interactions of cancer cells with adipocytes, macrophages, fibroblasts and mesothelial cells. However, as these stromal cells are constituents of all visceral fat pads, interactions with these cells may not fully explain the tropism of ovarian cancer cells for the omentum. Neutrophils act as the first line of defense in response to infection or malignancy. Because the omentum is the major site of neutrophil influx into the peritoneal cavity, we speculate that neutrophils direct ovarian cancer cells to the omental niche. This study focuses on a phenomenon in which neutrophils extrude sticky DNA webs called neutrophil extracellular traps (NETs). NETs were originally discovered to trap microbes in infectious diseases but very little is known about the significance of NETs in cancer. Based on our preliminary studies, we hypothesize that ovarian cancer cells induce neutrophils to form NETs in the omentum, and that omental metastasis stems in part from entrapment of cancer cells by NETs in the omental niche. In this project, we will determine whether (1) ovarian cancers induce NET formation in the pre-metastatic omental niche, (2) omental metastasis of ovarian cancer depends on NET formation and (3) omental metastasis is decreased by treatment with agents that inhibit NETs. These aims will be accomplished by evaluating patient clinical specimens, mouse tumor models and genetically modified mice that are defective in NET formation. Our study will provide new and provocative insights into the mechanisms that drive the propensity of ovarian cancer to colonize the omentum and the potential of repurposing NET-inhibiting agents for ovarian cancer therapy.

肠梗阻是卵巢癌女性死亡的主要原因，通常源于卵巢癌的生长。网膜上的肿瘤，网膜是一个从胃里悬出来的脂肪垫。本项目的目标是确定导致卵巢癌细胞在网膜上植入的机制，总体目标是为这种致命疾病找到更有效的治疗方法以前关于卵巢癌转移的研究主要集中在研究癌细胞与脂肪细胞、巨噬细胞、成纤维细胞和间皮细胞然而，由于这些基质细胞是所有内脏脂肪垫的组成部分，这些细胞可能不能完全解释卵巢癌细胞对网膜的向性。中性粒细胞作为是应对感染或恶性肿瘤的第一道防线。由于大网膜是中性粒细胞的主要部位，当中性粒细胞流入腹膜腔时，我们推测中性粒细胞将卵巢癌细胞引导至网膜龛。这项研究的重点是一种现象，即中性粒细胞挤出粘性的DNA网称为中性粒细胞细胞外陷阱（NET）。NET最初被发现用于捕获感染性疾病中的微生物，关于NETs在癌症中的重要性知之甚少。基于我们的初步研究，我们假设卵巢癌细胞诱导中性粒细胞在网膜中形成NETs，网膜转移源于部分原因是NETs将癌细胞截留在网膜龛中。在这个项目中，我们将确定是否 (1)卵巢癌在转移前网膜龛中诱导NET形成，（2）卵巢癌的网膜转移，卵巢癌依赖于NET的形成，（3）通过药物治疗可以减少网膜转移抑制NET。这些目标将通过评价患者临床标本、小鼠肿瘤 NET形成缺陷的模型和转基因小鼠。我们的研究将提供新的和对卵巢癌倾向于定植于网膜的机制的启发性见解以及重新利用NET抑制剂用于卵巢癌治疗的潜力。