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Table 3 Summary the major effect of the studies describing NETs in CRC

From: The emerging role of neutrophilic extracellular traps in intestinal disease

Study design Cell type Potential mechanisms to induce NET formation The role of NET in tumor progression Frist author, References
In vivo and in vitro Murine colorectal (MC38) cells, HCT116, Hepa1-6, and Huh7 cell lines Increased citrullinated histones and circulating MPO-DNA levels were related to poor survival of CRC patients NETs can directly alter the metabolic programming of cancer cells to increase tumor growth and shorter survival time Yazdani et al. [129]
In vivo, in vitro nd ex vivo Human colorectal cell line HCT116 or luciferase-labeled HCT116 cells TLR9 and the mitogen-activated protein kinase signaling pathway LPS-induced formation of NETs in promoting the development of tumors and metastasis Wang et al. [130]
In vitro and Ex vivo Human acute myeloid leukemia (AML) cells, Caco-2 cells Confirmed presence of NETs within the primary tumor sites of CRC and gradually dispersed to the tumor boundary, particularly to nearby metastatic lymph nodes Arelaki et al. [122]
In vivo and in vitro DKs-8(WT allele) cells and DKO-1 (KRASmutant)cells Exoxsomes from KRAS mutant CRC increase IL-8 production and provoke NET formation Released NETs increase CRC cells growth Shang et al. [131]
In vivo, in vitro,and Ex vivo Human hepatocellular carcinoma, human cell line HT29, mice cell line MC38 Elevated tumorous interleukin (IL)-8 expression triggered by NETs and overproduced IL-8 in turn activate neutrophils towards NETs formation Increased NETs boosted tumorous proliferation and invasion and contributed to onset of CRC liver metastasis Yang et al. [132]
In vivo and in vitro Human colon carcinoma cell line (HT-29), murine colon carcinoma subline with low CEACAM1 expression (MC38CC1-),murine colon carcinoma subline stably transfected with CEACAM1 long isoform[MC38CC1L] NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction NETs can promote colon carcinoma cell adhesion, migration and metastasis Rayes et al. [133]
In vivo and in vitro Murine Lewis Lung carcinoma cell subline H59, Murine colon carcinoma cell line MC38 Primary colon cancer cells provoked NETs generation Prime adhesion of CTCs to the liver and degradation of NETs decreased CRC cell adhesion and spontaneous metastasis to the liver and lung Rayes et al. [118]
In vivo and Ex vivo human colon cancer cell line HCT116, The transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK-β-parvin pathway to enhance cell motility A transmembrane DNA receptor that mediates NET-dependent metastasis Yang et al. [136]
In vivo and in vitro Human hepatoma cell line HepG2, murine colon carcinoma MC38 Neutrophil infiltration and NET formation reduced by adeno-associated virus (AAV) based DNase I gene therapy Reduced liver metastasis Xia et al. [137]
Ex vivo Human umbilical vein endothelial cells (HUVECs) platelets from CRC patients stimulated healthy neutrophils to extrude NETs, which could be inhibited by the depletion of HMGB1 NETs induce the procoagulant activity PCA and promote hypercoagulable state in CRC Zhang et al. [142]
Guglietta et al. [139]
In vivo, in vitro,and Ex vivo MC38 and Luciferase-expressing MC38 cells (MC38/Luc) NET triggered HMGB1 release and activated TLR9-dependent pathways NETs further fuel cancer cells adhesion, proliferation, migration, and invasionthe and reduce more than fourfold disease free survival Tohme et al. [128]
Ex Vitro Systemic neutrophils were isolated from human   Adverse patient outcomes were associated with increased preoperative NETs production Richardson et al. [142, 143]