The role of neutrophils in innate immunity is well known, but only recently they have been linked to other phenomena such as thrombosis and hemostasis. As a result, they emerge as key players in cancer progression and thrombus generation.
Neutrophils are the first immune cells recruited to inflammatory sites and resist circulating pathogens with their microbicidal activity. A chemokine gradient recruits circulating neutrophils to extra-vascular inflammatory sites .
Neutrophils and cancer
Neutrophils and tumor cells influence each other, and neutrophils can play a role in cancer development. For example, neutrophils enhance the secretion of chemokines during cancer development, and cancer cells secrete chemokines that induce neutrophils to migrate to the primary tumor .
Tumor-associated neutrophils are found at the tumor margins in the early stages of cancer and are divided into two populations: N1 and N2. N1 populations seem to have anti-tumor behavior, while N2 populations have pro-tumor behavior. Tumor cells can secrete cytokines that induce the switch of neutrophils from N1 to N2 type. In this way, the tumor can modulate the balance of N1–N2 neutrophils in favor of pro-tumoral N2 type .
Pro-tumoral N2 neutrophils can produce reactive oxygen species and reactive nitrogen species, which create DNA damage and genetic instability, potentially initiating the tumor process. In addition, they can secrete mediators into the tumoral microenvironment to induce angiogenesis and support tumor growth .
Finally, they play a key role in forming metastases by secreting matrix metallopeptidase 9 (MMP9) and neutrophil elastase to favor the remodeling of the extracellular matrix necessary for tumor progression. Moreover, N2 neutrophils secrete inflammatory cytokines that promote cancer cell migration and invasion .
Neutrophils and thrombosis
Neutrophils can influence thrombus formation in several ways.
1) On their membrane, they express tissue factor (TF), a procoagulant protein critical to cancer-associated thrombosis (CAT). TF promotes the extrinsic coagulation pathway by binding and stabilizing factor VII, activating downstream factors IX and X, and inducing thrombin and fibrin formation .
2) They can release microvesicles (MVs) that can promote thrombosis. MVs are small membrane vesicles released during cellular activation and have important roles in pathological conditions such as cancer . For example, they facilitate the formation of coagulation complexes and promote the ability of TF to initiate coagulation . In addition, neutrophil-derived MVs may contain myeloperoxidase (MPO), which plays a role in thrombus propagation .
4) They can also enhance thrombus formation through production of neutrophil extracellular traps (NETs). NETs are fibers of DNA and histones (chromatin) coated with antimicrobial proteins, such as MPO, cathepsin G and neutrophil elastase. Their formation is catalyzed by peptidyl-arginine deiminase 4 (PAD4), and neutrophils release them into the extracellular environment in defense against pathogens. NETs entrap and eliminate (through antimicrobial proteins) the pathogen, thereby preventing further spread in the host .
When trapping pathogens, NETs can also trap platelets, which are essential players in thrombosis. In addition, NETs entrap other key players of the coagulation cascade, such as von Willebrand factor (vWF), fibronectin and fibrinogen. The interaction between these molecules and platelets can induce platelet aggregation .
Finally, NETs can also secrete functional TF, which initiates the extrinsic coagulation pathways, leading to thrombus formation .
NETs, neutrophils and cancer
NETs can support neutrophils’ pro-tumoral role as they are involved in tumor growth and dissemination and the awakening of dormant cancer cells.
NETs and tumor growth and metastasis
NETs promote tumor cell growth by enhancing their mitochondrial functions . Additionally, they can facilitate metastasis in three ways:
- NETs might trap circulating cancer cells at the dissemination site, facilitating the adhesion of circulating tumor cells to form metastases .
- They may increase local vascular permeability that facilitates the extravasation of cancer cells into the surrounding tissues .
- NETs can act as a chemotactic factor, attracting cancer cells .
NETs and awakening of dormant cancer cells
Newly disseminated tumor cells that disseminated into distant organs can enter a state of dormancy that can last for weeks, months, even years, or decades before forming metastasis. However, these cells will eventually exit the quiescent state and produce metastasis, and NETs can initiate the reactivation of dormant tumor cells. The exact mechanism is unknown, but in mouse models, NE and MMP9 released by NETs can cleave laminin and induce the proliferation of dormant cancer cells .
NETs and CAT
Increased plasma levels of cell-free citrullinated histone H3, a marker of NETs release, in patients with cancer is associated with higher rates of venous thromboembolism . In addition, in patients with pancreatic cancer, elevated plasma circulating levels of histone–DNA complexes and cell-free DNA (markers of NETs) correlated with increased levels of thrombin generation and platelet microparticles .
In patients with gastric cancer or newly diagnosed colorectal cancer, increased NETs formation correlated with increased levels of thrombin–antithrombin complexes (TAT) and D-dimer [10, 11].
Neutrophils, specifically NETs, seem to play a pivotal role in cancer progression, metastasis, and CAT. Therefore, NETs and NETs markers might be potential therapeutic targets to prevent cancer progression, metastasis, and CAT. However, the clinical applicability of such an approach needs further investigation.
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