Abstract 1491: The enhanced formation of neutrophil extracellular traps (NETs) may contribute to the exacerbation of peritoneal metastasis in a diabetic host

Abstract

Abstract Background: Diabetes is associated with increased risk of cancer development and progression. Recent studies have shown that neutrophils in diabetic patients are prone to forming neutrophil extracellular traps (NETs) which have been reported to capture circulating cancer cells, leading to the promotion of liver and lung metastasis. This study aims to clarify the causative relationship between NETs and the peritoneal metastasis (PM) in diabetic condition. Methods: Outcome of the diabetic patients who received curative gastrectomy for gastric cancer from 2010 to 2021 in our institute was comparatively investigated with those without diabetes. Neutrophils were isolated from the bone marrow from C57BL/JHamSlc-ob/ob mouse (type 2 diabetes model) and wild type mouse using Ly6G-based positive immunomagnetic selection. The neutrophils were stimulated with 100nM of PMA for 4 hours and NETs formation was evaluated by the addition of Sytox Green under fluorescent microscope. A mouse gastric cancer cell, YTN16P (5 × 105 cells) was intraperitoneally (IP) injected, the number of metastatic nodules on mesentery was comparatively evaluated two weeks later. Results: Disease-free survival (p=0.004, HR=1.65) and overall survival (p=0.035, HR=1.46) of 203 diabetic patients were significantly worse those of 975 non-diabetic patients. Neutrophils isolated from ob/ob mice produced markedly increased NETs than that from wild-type mice. NETs produced by neutrophils obtained from the peritoneal cavity of ob/ob mice after IP injection of a 9% casein solution effectively captured many YTN16P in vitro. The concentration of double strand DNA (dsDNA) in plasma in ob/ob mice compared with their counterparts (676ng/mL vs 590ng/mL, p=0.036, n=3). The number of PM in ob/ob mice was significantly more than that in wild-type controls (39.1 vs 15.5, p=0.027, n=10). Conclusion: Enhanced NETs formation in diabetic conditions may be associated with an increased risk of PM in gastric cancer. Citation Format: Rei Takahashi, Hideyuki Ohzawa, Yuki Kaneko, Misaki Matsumiya, Yurie Futoh, Kohei Tamura, Kazuya Takahashi, Yuki Kimura, Akira Saito, Hideyo Miyato, Naohiro Sata, Joji Kitayama. The enhanced formation of neutrophil extracellular traps (NETs) may contribute to the exacerbation of peritoneal metastasis in a diabetic host [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1491.