Neutrophils, Cancer and Thrombosis: The New Bermuda Triangle in Cancer Research

Abstract

Spontaneous venous thrombosis is often the first clinical sign of cancer, and it is linked to a worsened survival rate. Traditionally, tumor-cell induced platelet activation has been the main actor studied in cancer-associated-thrombosis. However, platelet involvement alone does not seem to be sufficient to explain this heightened pro-thrombotic state. Neutrophils are emerging as key players in both thrombus generation and cancer progression. Neutrophils can impact thrombosis through the release of pro-inflammatory cytokines and expression of molecules like P-selectin and Tissue Factor (TF) on their membrane and on neutrophil-derived microvesicles. Their role in cancer progression is evidenced by the fact that patients with high blood-neutrophil counts have a worsened prognosis. Tumors can attract neutrophils to the cancer site via pro-inflammatory cytokine secretions and induce a switch to pro-tumoral (or N2) neutrophils, which support metastatic spread and have an immunosuppressive role. They can also expel their nuclear contents to entrap pathogens forming Neutrophil Extracellular Traps (NETs) and can also capture coagulation factors, enhancing the thrombus formation. These NETs are also known to have pro-tumoral effects by supporting the metastatic process. Here, we strived to do a comprehensive literature review of the role of neutrophils as drivers of both cancer-associated thrombosis (CAT) and cancer progression.

Extracellular Traps Increase Burden of Bleeding by Damaging Endothelial Cell in Acute Promyelocytic Leukaemia

“…ETs can damage organs through direct cell damage and uncontrolled inflammatory response in diseases such as sepsis, acute lung injury and acute liver injury ( 5 ). The active components of ETs promote coagulation, interfere with the anticoagulation system, and provide a scaffold for PLTs and erythrocytes adhesion and fibrin deposition to facilitate thrombosis ( 6 ). Studies have found that coronary thrombi contain a large amount of ETs, and the increase of ETs level is related to the infarct size of acute myocardial ( 7 ).…”

Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

“…Via CLEC1A, HRG also stimulates neutrophils to superior performance as seen in cancer-inhibiting N1-neutrophils, which exhibit prolonged longevity [ 36 ], implying that HRG may sustain neutrophils in an N1 state. On the other hand, another type of neutrophils called N2 neutrophils appear to be tightly involved in cancer progression through the active formation of neutrophil extracellular traps (NETs) [ 37 ], which release abundant HMGB1 extracellularly as well as S100A8/A9 [ 38 , 39 ] and our unpublished data. Thus, it seems reasonable to speculate that HRG may also function to block cancer activation by regulating young neutrophils.…”

A prospective marker for the prediction of postoperative deep venous thrombosis: Neutrophil extracellular traps

“…Previous studies have shown that neutrophils act as an indicator of inflammation and contribute to DVT by releasing NETs and neutrophil histone modifications ( Brill et al, 2012 ; Brinkmann, 2018 ). Notably, there is controversy regarding the relationship between neutrophil counts and venous thrombosis ( Martos et al, 2020 ; Ferrer-Marin et al, 2021 ; Langiu et al, 2022 ). Studies suggested that NETs rather than increased neutrophil counts are crucial in promoting DVT formation ( Noubouossie et al, 2019 ).…”