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 | Â | Adverse patient outcomes were associated with increased preoperative NETs production |