Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.
Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL.
J Exp Med. 2019 Jan 7;216(1):176-194. doi: 10.1084/jem.20181170. Epub 2018 Dec 19.
Ovarian cancer preferentially metastasizes to the omentum, a fatty tissue characterized by immune structures called milky spots, but the cellular dynamics that direct this tropism are unknown. Here, we identified that neutrophil influx into the omentum is a prerequisite premetastatic step in orthotopic ovarian cancer models. Ovarian tumor-derived inflammatory factors stimulated neutrophils to mobilize and extrude chromatin webs called neutrophil extracellular traps (NETs). NETs were detected in the omentum of ovarian tumor-bearing mice before metastasis and of women with early-stage ovarian cancer. NETs, in turn, bound ovarian cancer cells and promoted metastasis. Omental metastasis was decreased in mice with neutrophil-specific deficiency of peptidylarginine deiminase 4 (PAD4), an enzyme that is essential for NET formation. Blockade of NET formation using a PAD4 pharmacologic inhibitor also decreased omental colonization. Our findings implicate NET formation in rendering the premetastatic omental niche conducive for implantation of ovarian cancer cells and raise the possibility that blockade of NET formation prevents omental metastasis.
卵巢癌优先转移到腹膜，腹膜是一种富含免疫结构的脂肪组织，称为乳斑，但指导这种趋向性的细胞动力学尚不清楚。在这里，我们发现中性粒细胞流入腹膜是卵巢癌原位模型中预先转移的必要前提步骤。卵巢肿瘤衍生的炎症因子刺激中性粒细胞动员并挤出称为中性粒细胞细胞外陷阱（NETs）的染色质网。在卵巢肿瘤荷瘤小鼠和早期卵巢癌患者的腹膜中检测到 NETs。反过来，NETs 结合卵巢癌细胞并促进转移。在中性粒细胞特异性缺乏肽基精氨酸脱亚氨酶 4（PAD4）的小鼠中，NET 的形成减少了腹膜转移，PAD4 是 NET 形成所必需的酶。使用 PAD4 药理学抑制剂阻断 NET 形成也减少了腹膜定植。我们的研究结果表明 NET 的形成使得预先转移的腹膜生态位有利于卵巢癌细胞的植入，并提出了阻断 NET 形成可防止腹膜转移的可能性。
