Neutrophil Extracellular Traps in Digestive Cancers: Warrior or Accomplice

Abstract

Characterized as a complex of extracellular DNA fibers and granule proteins, neutrophil extracellular traps (NETs) are generated specifically by neutrophils which play a critical role in host defense and immune regulation. NETs have been initially found crucial for neutrophil anti-microbial function. Recent studies suggest that NETs are involved in tumorigenesis and cancer progression. However, the function of NETs in cancer remains unclear, which might be due to the variation of research models and the heterogeneity of cancers. Although most of malignant tumors have similar biological behaviors, significant differences indeed exist in various systems. Malignant tumors of the digestive system cause the most incidence and mortality of cancer worldwide. In this review, we would focus on research developments on NETs in digestive cancers to provide insights on their role in digestive cancer progression and future research directions.

Keywords: cancer; digestive system; immunity; neutrophil extracellular trap; targeted therapy.

Figure 1

The mechanisms by which NETs directly promote tumor progression. (A) In several types of stimuli in tumor tissues, neutrophils expel their DNA and cytoplasmic proteins to form extracellular structure to participate in tumor progression. NETs-DNA could interact with RAGE and CCDC25 respectively to be involved in the transduction of intracellular tumor-promoting signals, which facilitate tumor progression. Additionally, NETs associated protein components, such as NE, MMP9 and HMGB1, also could cooperate with respective receptor to stimulate downstream pathways to fuel the malignancy of tumors. Question marks (?) represent relevant functional components of NETs and related receptors that have not been clearly stated (especially the right side of red dotted line). (B) Components of NETs involved in the cytokine release, proliferation, invasion, migration and metastasis of tumor cells through respective relevant receptors.

Figure 2

The main effect of NETs on digestive cancers. Although the effect of NETs on OSCC and colon carcinoma remains unclear, NETs mainly play a pro-tumor role in esophageal, gastric, pancreatic, liver and biliary cancers.