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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：
10360586
负责人：
Honami Naora
金额：
$ 35.35万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10360586
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 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患者死亡的主要原因，通常源于肿瘤的生长