Neutrophils Facilitate Ovarian Cancer Premetastatic Niche Formation in the Omentum

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Dec 21

PMID 30567719

Citations 236

Authors

Wonjae Lee

Song Yi Ko

Muhaned S Mohamed

Hilary A Kenny

Ernst Lengyel

Honami Naora

Affiliations

Soon will be listed here.

Abstract

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.

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