Neutrophil Extracellular Traps and Macrophage Extracellular Traps Predict Postoperative Recurrence in Resectable Nonfunctional Pancreatic Neuroendocrine Tumors

Xu, Shuaishuai; Li, Hao; Li, Tianjiao; Li, Shuo; Xia, Huanyu; Long, Jiang; Wu, Chifei; Wang, Wenquan; Zhang, Wuhu; Gao, Heli; Han, Xuan; Ye, Long‐Yun; Lin, Xuan; Xu, Huaxiang; Lei, Yu; Liu, Liang

doi:10.3389/fimmu.2021.577517

Cited by 15 publications

(18 citation statements)

References 55 publications

(59 reference statements)

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“…High METs predicted the worst prognosis for CC patients. This result was consistent with a previous study showing that macrophages participate in the immune response of nonfunctional pancreatic neuroendocrine tumors in the form of METs ( 24 ). However, they did not confirm this breakthrough conclusion through in vivo and in vitro experiments.…”

Section: Discussionsupporting

confidence: 94%

“…Extracellular structures exceeding 20 μm in length with DNA-, CD68- and H3Cit-positive staining were calculated, manually. The mean value was regarded as the final score of macrophages infiltration or METs formation in the tumor of each patient, as described ( 24 ).…”

Section: Methodsmentioning

confidence: 99%

“…METs have been reported to be involved in the response process of bacteria and their toxins, the lipid-rich lesions in atherosclerosis, and acute kidney injury (20)(21)(22)(23). However, the research about METs in the field of cancer is limited to nonfunctional pancreatic neuroendocrine tumors, and there is little relevant research in CRC (24). About 70% of CC patients present with macrophage infiltration, but its role in the progression of CC is still controversial.…”

Section: Introductionmentioning

confidence: 99%

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Interaction Between Macrophage Extracellular Traps and Colon Cancer Cells Promotes Colon Cancer Invasion and Correlates With Unfavorable Prognosis

et al. 2021

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BackgroundMacrophage extracellular traps (METs) and tumor-infiltrating macrophages contribute to the progression of several diseases. But the role of METs and tumor-infiltrating macrophages in colon cancer (CC) has not been illuminated. In this study, we aimed to clarify the prognostic value of METs for CC patients and to explore the interaction between CC cells and METs in vitro and in vivo.MethodsA training cohort consisting of 116 patients and a validation cohort of 94 patients were enrolled in this study. Immunofluorescence (IF) staining was conducted to determine METs formation in CC patients. Cox regression was used to perform prognostic analysis and screen out the best prognostic model. A nomogram was established to predict 5-year overall survival (OS). The correlation between METs with clinicopathological features and inflammatory markers was analyzed. The formation of METs in vitro was detected by SYTOX® green and IF staining, and the effect of METs on CC cells was detected by transwell assays. PAD2-IN-1, a selective inhibitor of peptidylarginine deiminase 2 (PAD2), was introduced to destroy the crosstalk between CC cells and METs in vitro and in vivo.ResultsMETs levels were higher in CC tissues and were an independent prognostic factor for CC patients. The prognostic model consisting of age, tumors local invasion, lymph node metastasis and METs were confirmed to be consistent and accurate for predicting the 5-year OS of CC patients. Besides, METs were correlated with distant metastasis and inflammation. Through in vitro experiments, we confirmed that there was a positive feedback loop between CC cells and METs, in that METs promoted the invasion of CC cells and CC cells enhanced the production of METs, in turn. This interaction could be blocked by PAD2-IN-1 inhibitors. More importantly, animal experiments revealed that PAD2-IN-1 inhibited METs formation and CC liver metastasis in vivo.ConclusionsMETs were the potential biomarker of CC patient prognosis. PAD2-IN-1 inhibited the crosstalk between CC cells and METs in vitro and in vivo, which should be emphasized in CC therapy.

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Section: Discussionsupporting

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interaction Between Macrophage Extracellular Traps and Colon Cancer Cells Promotes Colon Cancer Invasion and Correlates With Unfavorable Prognosis

et al. 2021

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“…MET formation may possibly correlate with these pathological signs and the severity of breast cancer. Recently Xu et al., identified several sources of NETs and METs in tumor tissues isolated from patients with pancreatic neuroendocrine cancer ( 200 ). The patients with high levels of NETs and METs have a postoperative cancer recurrence ( 200 ), indicating that these ETs may generate anti-cancer resistance mechanisms, leading to the cancer relapse.…”

Section: Monocyte and Macrophage Extracellular Trapsmentioning

confidence: 99%

Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies

et al. 2022

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Extracellular DNA may serve as marker in liquid biopsies to determine individual diagnosis and prognosis in cancer patients. Cell death or active release from various cell types, including immune cells can result in the release of DNA into the extracellular milieu. Neutrophils are important components of the innate immune system, controlling pathogens through phagocytosis and/or the release of neutrophil extracellular traps (NETs). NETs also promote tumor progression and metastasis, by modulating angiogenesis, anti-tumor immunity, blood clotting and inflammation and providing a supportive niche for metastasizing cancer cells. Besides neutrophils, other immune cells such as eosinophils, dendritic cells, monocytes/macrophages, mast cells, basophils and lymphocytes can also form extracellular traps (ETs) during cancer progression, indicating possible multiple origins of extracellular DNA in cancer. In this review, we summarize the pathomechanisms of ET formation generated by different cell types, and analyze these processes in the context of cancer. We also critically discuss potential ET-inhibiting agents, which may open new therapeutic strategies for cancer prevention and treatment.

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“…Additionally, the infiltration of CD68 + macrophages or CD163 + M2-polarized macrophages was associated with the high risk of recurrence as an independent disease-specific survival prognosis factor for postoperative patients with pancreatic NETs [ 19 , 20 , 21 ]. Notably, macrophage extracellular traps, as a form of macrophage death, could also predict recurrence prognosis in nonfunctional pancreatic NETs [ 22 ]. However, macrophages do not always reflect the outcomes of different treatments.…”

Section: Innate Immune Cellsmentioning

confidence: 99%

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

Chen

et al. 2022

Cancers

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Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.

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Neutrophil Extracellular Traps and Macrophage Extracellular Traps Predict Postoperative Recurrence in Resectable Nonfunctional Pancreatic Neuroendocrine Tumors

Cited by 15 publications

References 55 publications

Interaction Between Macrophage Extracellular Traps and Colon Cancer Cells Promotes Colon Cancer Invasion and Correlates With Unfavorable Prognosis

Interaction Between Macrophage Extracellular Traps and Colon Cancer Cells Promotes Colon Cancer Invasion and Correlates With Unfavorable Prognosis

Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

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