DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth

Abstract

Neutrophil extracellular trap (NET) formation results in the expulsion of granulocyte proteins and DNA into the extracellular space. This process is mediated by the enzyme peptidyl arginine deiminase 4 (PADI4) and translocation of elastase to the nucleus. NET formation, marked by increased levels of extracellular DNA, promotes pancreatic cancer proliferation and metastasis. Mice deficient in Padi4 demonstrate decreased pancreatic tumor growth, associated with a reduction in circulating extracellular DNA levels, diminished pancreatic stromal activation and improved survival in murine orthotopic pancreatic adenocarcinoma. Transplantation of Padi4 −/− bone marrow into genetically engineered mice with Kras driven pancreatic adenocarcinoma (Pdx1-Cre:Kras G12D/+ , KC mice) limits the frequency of invasive cancers when compared with syngeneic controls. DNA from neutrophils activates pancreatic stellate cells that form dense, fibrous stroma which can promote and enable tumor proliferation. DNase treatment diminishes murine tumor growth and stromal activation to reverse the effect of NETs within the tumor microenvironment. Furthermore, deletion of the receptor for advanced glycation end products (RAGE) in pancreatic stellate cells abrogates the effects of DNA in promoting stellate cell proliferation and decreases tumor growth. Circulating neutrophil-derived DNA correlates with the stage in patients with pancreatic ductal adenocarcinoma, confirming the role of NETs in human pancreatic cancer. These findings support further investigation into targeting of NETs, PADI4 and extracellular DNA as a potential treatment strategy in patients with pancreatic cancer. Trial Registration: This study reports correlative data from a clinical trial registered with clinicaltrials. gov, NCT01978184 (November 7, 2013).

Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming

“…Cellular debris and contents can be recognized by the corresponding PRRs on immune cells to trigger cancer-related inflammation, which is identified as DAMPs including HMGB1, hot shock protein, hyaluronan, fibrinogen, nucleic acid fragments, and so on ( Patidar et al, 2018 ; Miller-Ocuin et al, 2019 ; Zhang B. et al, 2019 ). After NACRT, DAMP overproduction acquired a purposeful immune response and longer survival of PDAC patients ( Murakami et al, 2017 ).…”

Cancer Cells Resistance Shaping by Tumor Infiltrating Myeloid Cells

“…The enhancement of non-small cell lung cancer cells proliferation is also favored by elastase that is produced following their interaction with neutrophils as well as the production of immunosuppressive PGE2 [ 145 ]. NET overproduction was also involved in promoting tumor cells proliferation, but also migration and invasion, favoring the crosstalk between glioma cells and the TME by regulating the HMGB1/RAGE/IL-8 axis [ 146 ] or by activating pancreatic tumor growth through the DNA releases from NET [ 147 ].…”

The Neutrophil: Constant Defender and First Responder

“…However, the role of PMNs in cancer is complex, and they are not only capable of killing tumor cells but also promoting tumor growth ( 121 , 122 ). Although PMNs have anti-tumor potential ( 7 ), tumors can subvert PMN function ( 8 , 54 , 55 ), including NET formation ( 123 ), to promote tumor growth. PMNs can also contribute to metastasis ( 9 , 124 ).…”