Table 1.
Pathophysiological role of ETs in cancer.
| Biological effect | ET type | Cancer model | Underlying mechanism | Ref. |
|---|---|---|---|---|
| Tumor growth | NETs | Colorectal cancer In vitro: DKs-8, DKO-1 cells In vivo: Apc-KRASG12D mouse model |
Cancer cells transfer KRAS mutations through exosomes to neutrophils and induce neutrophil recruitment and NETosis via upregulation of IL8, promoting cancer cell proliferation. | (96) |
| Colorectal cancer In vitro: MC38 cells In vivo: syngeneic subcutaneous MC38 cancer model |
NET-associated PD-L1 induces T cell exhaustion and enhances tumor growth. | (109) | ||
| Hepatocellular carcinoma In vivo: DEN-HFCD, STAM mouse models |
NETs enhance differentiation of regulatory T cells by promoting mitochondrial oxidative phosphorylation in naive CD4+ T cells via TLR4, amplifying tumor burden. | (110) | ||
|
Migration, Invasion;
EMT |
NETs | Breast cancer In vitro: MCF7 cells |
NETs enhance the expression of EMT markers ZEB1, Snail and fibronectin, cancer stem cell marker CD44, proinflammatory mediators, such as IL1β, IL6, IL8, CXCR1, MMP2 and MMP9. | (86) |
| Gastric cancer In vitro: AGS cells |
NETs enhance cancer cell migration and induce EMT; downregulation of E-cadherin and upregulation of vimentin expression. | (87) | ||
| Pancreatic cancer In vitro: BxPC3, MIA, PaCa2, PANC1 cells In vivo: subcutaneous MIA and PaCa2 xenograft cancer models Ex vivo: human PDAC |
Release of IL1β during NETosis activates EGFR/ERK pathway, leading to the EMT; downregulation of E-cadherin and upregulation of Snail, N-cadherin and vimentin expression. |
(88) | ||
| Colorectal cancer In vitro: DKs-8, DKO-1 cells In vivo: Apc-KRASG12D mouse model |
KRAS mutant exosomes from tumor cells induce NETosis via IL8, leading to the enhanced cancer cell migration and invasion. | (96) | ||
| Breast cancer In vitro: 4T1, 4T07, BT-549 and C3(1)-Tag cells |
Cancer cell-derived G-CSF primes neutrophils, resulting in lytic NETosis; cathepsin G enhances NET-mediated cancer cell invasion among other NET-associated proteins. | (14) | ||
| Pancreatic cancer In vitro: AsPC-1 cells |
NETs induce cancer cell migration via TLR2 and TLR4. | (16) | ||
| METs | Colon cancer In vitro: HCT116 and SW480 cells Ex vivo: human colon cancer |
Cancer cells promote MET formation via PAD2; METs interact with tumor cells and enhance tumor cell invasion. | (201) | |
| Metastasis | NETs | Breast cancer In vitro: 4T1 series, AT3, MDA-MB-231 and sublines In vivo: syngeneic orthotopic (4T1 series, AT3), xenograft (MDA-MB-231 and sublines) cancer models Ex vivo: human breast cancer |
Tumor-derived cathepsin C (CTSC) triggers CTSC-PR3-IL1β axis in neutrophils, upregulating IL6 and CCL3 synthesis. CTSC-PR3-IL1β induces ROS production and NET formation which degrade thrombospondin-1, thereby supporting metastatic growth of lung cancer cells. | (95) |
| Breast cancer In vivo: 4T1 experimental and spontaneous breast cancer metastasis models |
NETs enhance lung metastasis. | (14) | ||
| Breast cancer and colon cancer In vitro: MDA-MB-231, MCF-7 and HCT116 cells In vivo: syngeneic (4T1) and xenograft (MDA-MB-231) orthotopic and intrasplenic (MMTV-PyMT mice and E0771 cells) cancer models Ex vivo: human breast and colon cancer |
CCDC25 on cancer cell surface acts as a sensor and binding partner for NET-DNA; binding leads to activation of ILK–β-parvin–RAC1–CDC42 cascade, cytoskeleton remodeling and formation of distant metastases. | (18) | ||
| Breast cancer In vitro: D2.0R, MCF7 cells In vivo: syngeneic (D2.0R) and xenograft (MCF7) experimental breast cancer metastasis models |
NET-associated NE and MMP9 cleave laminin and degrade thrombospondin-1 leading to the activation of integrin α3β1 and FAK/ERK/MLCK/YAP signaling, resulting in reactivation of dormant cancer cells during tumor metastasis. | (108) | ||
| Colon, melanoma, lung and breast cancer In vitro: primary melanoma and LS174T, HT29 cells In vivo: syngeneic subcutaneous (4T1, LLC and HT29) and intradermic (B16OVA and 4T1) cancer models |
Cancer cells trigger NETosis by CXCR1 and CXCR2 activation; NETs protect tumor cells from contact with cytotoxic T cells and NK cells, promoting cancer cell dissemination and lung metastasis. | (105) | ||
| Lung cancer In vitro: A549 cells In vivo: experimental liver metastasis of A549 cells (intrasplenic injection into caecal ligation and puncture-induced sepsis model) |
Tumor- and NET-derived β1-integrin mediates adhesion of NETs to circulating tumor cells, facilitating cancer cell adhesion to the liver sinusoids. | (102) | ||
| Ovarian cancer In vitro: ES2 and ID8 cells In vivo: syngeneic (ID8) and xenograft (ES2), (intrabursal and intraperitoneal injection) cancer models |
Cancer-derived cytokines (IL8, G-CSF, GROα, GROβ) promote NETosis; NETs accumulate in premetastatic niche and enhance the formation of omental metastases. | (20) | ||
| METs | Colon cancer In vivo: MC38 experimental colon cancer metastasis model Ex vivo: human colon cancer |
Cancer cells promote MET formation via PAD2, enhancing the formation of liver metastases. | (201) | |
| Cancer-associated thrombosis | NETs | Chronic myelogenous leukemia (CML), breast and colon cancer In vivo: syngeneic orthotopic breast (4T1) and subcutaneous lung (LLC) and CML mouse models |
Cancer cells predispose neutrophils to form NETs via G-CSF, promoting microthrombosis in the lung. | (97) |
| Breast cancer In vivo: syngeneic orthotopic breast (4T1 and 67NR) models |
Cancer-derived G-CSF induces neutrophilia and NETosis, leading to the prothrombotic phenotype. | (113) | ||
| Glioma Ex vivo: human glioma |
Platelets of late-stage glioma patients induce NETosis via P-Selectin and NETs promote hypercoagulant state and thrombogenicity in endothelial cells. | (125) | ||
| Myeloproliferative neoplasms (MPN) In vivo: Jak2V617F mouse model Ex vivo: human MPN |
Jak2 V617F mutation stimulates NET formation and thrombosis in a PAD4-dependent manner. | (132) | ||
| Pancreatic cancer In vitro: AsPC-1 cells Ex vivo: pancreatic and biliary cancer |
Tumor cells induce NET generation in a cAMP- and thrombin-dependent, and ROS-independent manner; NETs enhance thrombin generation. | (16) | ||
| Pancreatic cancer Ex vivo: orthotopic (Panc02) cancer model, human pancreatic cancer |
NETs induce RAGE-dependent platelet aggregation and increase TF expression, thereby enhancing coagulation. | (127) | ||
| Pancreatic cancer In vitro: AsPC-1 cells |
Platelets primed by tumor cells induce rapid NET generation; NETs trap platelets and stimulate thrombus formation under shear conditions. |
(128) | ||
| Small intestine cancer In vivo and ex vivo: ApcMin/+ mouse model |
Inflammation-associated complement activation via neutrophil C3aR induces NETosis, hypercoagulation, and N2 neutrophil polarization in small intestine. | (130) | ||
|
Ex vivo: human solid cancers Prostate, liver, lung, bladder and breast |
Malignant tumors enhance NETosis via G-CSF, inducing microthrombosis and the occurrence of ischemic stroke with elevated troponin levels. | (134) | ||
| Secondary organ damage | NETs | Breast cancer and insulinoma In vivo: MMTV-PyMT and RIP1-Tag2 transgenic models |
Cancer cell-derived G-CSF induces systemic NETosis. NETs occlude kidney and heart vessels, inducing irregular blood flow, increased endothelial cell activation with upregulated expression of proinflammatory mediators, ICAM1, VCAM1, E-selectin, IL1β, IL6, and CXCL1. | (98) |
| Poor prognosis and therapeutic resistance | NETs | Bladder cancer In vitro: MB49, UM-UC3 cells In vivo: syngeneic heterotopic MB49 bladder cancer model Ex vivo: human bladder tumor |
Radiation induces HMGB1 release in tumor microenvironment, triggering NETosis through TLR4; NETs enhance resistance to radiotherapy by suppressing CD8+ T cell infiltration. | (111) |
| NETs, METs | Ex vivo: human pancreatic neuroendocrine tumors | Poor prognosis and postoperative recurrence of resected tumors. | (200) | |
| NETs,EETs | Ex vivo: human classic Hodgkin lymphoma, nodular sclerosis subtype | Eosinophilia and detection of NETs and EETs in lymph tumor tissues. Correlation between NET formation and fibrosis High expression of PAR-2 and nuclear p-ERK in cancer cells. Enhanced TF expression and procoagulancy in tumor-associated endothelium. |
(160) |
EMT, epithelial-mesenchymal transition; DEN-HFCD, diethylnitrosamine + choline-deficient, high-fat diet; STAM, Stelic Animal Model; MMTV-PyMT, mouse mammary tumor virus-polyoma middle tumor-antigen.