Autophagy sustains the survival and pro-tumorigenic effects of neutrophils in human cancer (P2053)

Abstract

Abstract Neutrophils are a common inflammatory infiltrate that are enriched predominantly in the peritumoral stroma of many human cancers. The underlying mechanisms, however, that allow tumor microenvironments to educate neutrophils in peritumoral stroma are largely unknown. Herein we showed that most neutrophils in peritumoral stroma areas, but not those within the blood vessels, expressed significant higher amount of autophagy-related LC3 protein. In consistence, exposure of neutrophils to culture supernatants from several types of solid tumor cells (TSN) resulted in a rapid up-regulation of autophagy in cells, an effect that could be inhibited by blocking the activation of Erk1/2, p38 and NF-κB signaling pathways. The increased autophagy in TSN-exposed neutrophils was associated with preserved mitochondria integrity, reduced production of mitochondrial reactive species and cleavage of Caspase 3, and attenuated apoptosis in these cells. Pretreatment with 3-methyladenine, a specific autophagy inhibitor, could effectively induce mitochondrial injury and subsequent apoptosis in neutrophils. Moreover, we provided evidence that the induction of autophagy markedly enhance the pro-tumorigenic activities of neutrophils by releasing higher amount of matrix metalloproteinase-9, hepatocyte growth factor, and oncostatin M. Thus, increased autophagy in tumor-associated neutrophils may represent a novel mechanism that links the inflammatory response to neoplastic metastasis.