Primary tumors induce neutrophil extracellular traps with targetable metastasis-promoting effects

Rayes, Roni F.; Mouhanna, Jack; Nicolau, Ioana; Giannias, Betty; Rousseau, Stéphane; Quail, Daniela F.; Walsh, Logan A.; Sangwan, Veena; Bertos, Nicholas; Cools-Lartigue, Jonathan; Ferri, Lorenzo; Spicer, Jonathan

doi:10.1172/jci.insight.128008

Cited by 167 publications

(177 citation statements)

References 55 publications

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“…Furthermore, tumor cells have been demonstrated to produce IL-8, attracting myeloid-derived suppressor cells (MDSC) and activating granulocytic MDSC to extrude DNA nets 145 . In addition, by applying intravital microscopy, a significant increase in the in vivo hepatic adhesion of intrasplenically injected lung or colon cancer cells was observed in the presence of NETs when compared with animals, in which NET formation had been prevented 146 . Although tumorinfiltrating neutrophils were rare in tissue specimens of epithelial ovarian cancer, both intact neutrophils and NETs were observed in tumors from 4 of 5 patients 147 .…”

Section: The Formation Of Extracellular Dna Traps In Cancermentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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Section: The Formation Of Extracellular Dna Traps In Cancermentioning

confidence: 99%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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“…Previous evidence in other cancer types has demonstrated that cancer-induced neutrophil ROS and NETs contribute to tumor proliferation, demonstrated in other cancer types [19][20][21]. However, the consequences of neutrophil activation and direct neutrophil-BM-PCa interactions on tumor growth have not been fully explored.…”

Section: Neutrophils Regulate Pca Growth In Vitro Independently Of Tgfβmentioning

confidence: 99%

Neutrophils are mediators of metastatic prostate cancer progression in bone

Costanzo-Garvey

Keeley

Case

et al. 2020

Cancer Immunol Immunother

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Bone metastatic prostate cancer (BM-PCa) significantly reduces overall patient survival and is currently incurable. Current standard immunotherapy showed promising results for PCa patients with metastatic, but less advanced, disease (i.e., fewer than 20 bone lesions) suggesting that PCa growth in bone contributes to response to immunotherapy. We found that: (1) PCa stimulates recruitment of neutrophils, the most abundant immune cell in bone, and (2) that neutrophils heavily infiltrate regions of prostate tumor in bone of BM-PCa patients. Based on these findings, we examined the impact of direct neutrophilprostate cancer interactions on prostate cancer growth. Bone marrow neutrophils directly induced apoptosis of PCa in vitro and in vivo, such that neutrophil depletion in bone metastasis models enhanced BM-PCa growth. Neutrophil-mediated PCa killing was found to be mediated by suppression of STAT5, a transcription factor shown to promote PCa progression. However, as the tumor progressed in bone over time, neutrophils from late-stage bone tumors failed to elicit cytotoxic effector responses to PCa. These findings are the first to demonstrate that bone-resident neutrophils inhibit PCa and that BM-PCa are able to progress via evasion of neutrophil-mediated killing. Enhancing neutrophil cytotoxicity in bone may present a novel therapeutic option for bone metastatic prostate cancer.

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“…Therefore, NETs may also exist in the GC microenvironment. In addition, a recent study reported significantly higher PB levels of NETs in 25 advanced esophagogastric adenocarcinoma patients than in 12 patients with local disease ( 15 ). Nevertheless, there is currently a lack of large-sample research data.…”

Section: Introductionmentioning

confidence: 99%

Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma

Zhang

et al. 2020

Front. Oncol.

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Neutrophils are a significant population of infiltrated immune cells in the tumor microenvironment. Neutrophil extracellular traps (NETs) are implicated in the biological behavior of many malignant tumors. NETs can be degraded into soluble nucleosomes, leading to the release of fragments containing DNA and granule proteins into the peripheral blood (PB). Using human gastric cancer (GC) biopsies and PB samples, we investigated the specific value of NETs in GC from a clinical perspective. In summary, the formation of NETs was discovered in the tissue microenvironment and PB of GC patients. The amounts of NETs and neutrophil accumulation decreased from tumor tissue to paratumor tissue. In addition, the level of NETs in the PB gradually declined through the following patient populations: advanced disease patients, preoperative patients, postoperative patients, benign disease patients, and healthy controls. The levels of NETs in the plasma and serum were significantly correlated. As a serum biomarker, NETs had a better diagnostic value than carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in GC. The neutrophil count and neutrophil to lymphocyte ratio (NLR) were significantly associated with the level of NETs in the PB. The existence of lymph node metastasis indicated a high level of NETs in the serum. Moreover, the level of NETs in the PB was inversely correlated with short-term efficacy in GC patients who had received advanced first-line treatment. The higher baseline level of NETs in the PB of patients with negative HER2 status was correlated with worse progression-free survival (PFS). And the level of NETs in the PB was a unfavorable independent prognostic factor for PFS in patients with advanced GC who had received first-line treatment. Thus, NETs have novel diagnostic, therapeutic predictive, and prognostic value in GC patients.

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Primary tumors induce neutrophil extracellular traps with targetable metastasis-promoting effects

Cited by 167 publications

References 55 publications

In vivo evidence for extracellular DNA trap formation

In vivo evidence for extracellular DNA trap formation

Neutrophils are mediators of metastatic prostate cancer progression in bone

Diagnostic, Therapeutic Predictive, and Prognostic Value of Neutrophil Extracellular Traps in Patients With Gastric Adenocarcinoma

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