Pre-metastatic Omental Niche Formation in Ovarian Cancer

肠梗阻是卵巢癌女性患者的主要死亡原因，通常源于卵巢癌的生长。 大网膜上的肿瘤，一种悬挂在胃上的脂肪垫。该项目的目标是确定 导致卵巢癌细胞植入大网膜的机制，其首要目标是 为这一致命疾病寻找更有效的治疗方法。以前对卵巢癌转移的研究已经 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，与 这些细胞可能不能完全解释卵巢癌细胞对大网膜的趋向性。中性粒细胞扮演着 应对感染或恶性疾病的第一道防线。因为大网膜是中性粒细胞的主要部位 中性粒细胞进入腹膜腔后，我们推测是中性粒细胞将卵巢癌细胞导向大网膜小窝。 这项研究的重点是中性粒细胞排出一种叫做中性粒细胞的粘性dna网络。 胞外陷阱(Net)。蚊帐最初被发现用来捕获传染病中的微生物，但非常 人们对Nets在癌症中的重要性知之甚少。根据我们的初步研究，我们假设 卵巢癌细胞诱导中性粒细胞在大网膜形成Net，大网膜转移源于 部分原因是由大网膜壁龛内的网络捕获癌细胞所致。在这个项目中，我们将确定是否 (1)卵巢癌在转移前的大网膜壁龛中诱导净形成；(2)大网膜转移 卵巢癌依赖于净形成；(3)药物治疗可减少大网膜转移 这抑制了篮网。这些目标将通过评估患者的临床标本、小鼠肿瘤来实现 网络形成有缺陷的模型和转基因小鼠。我们的研究将提供新的和 对驱使卵巢癌倾向于大网膜定植的机制的具有挑衅性的见解 以及用于卵巢癌治疗的再利用网络抑制剂的潜力。

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.