The dual role of neutrophils in cancer

For the past decade, the role and importance of neutrophils in cancer is being increasingly appreciated. Research has focused on the ability of cancer-related neutrophils to either support tumor growth or interfere with it, showing diverse mechanisms through which the effects of neutrophils take place. In contrast to the historic view of neutrophils as terminally differentiated cells, mounting evidence has demonstrated that neutrophils are a plastic and diverse population of cells. These dynamic and plastic abilities allow them to perform varied and sometimes opposite functions simultaneously. In this review, we summarize and detail clinical and experimental evidence for, and underlying mechanisms of, the dual impact of neutrophils' functions, both supporting and inhibiting cancer development. We first discuss the effects of various basic functions of neutrophils, namely direct cytotoxicity, secretion of reactive oxygen species (ROS), nitric oxide (NO) and proteases, NETosis, autophagy and modulation of other immune cells, on tumor growth and metastatic progression. We then describe the clinical evidence for pro- vs anti-tumor functions of neutrophils in human cancer. We believe and show that the "net" impact of neutrophils in cancer is the sum of a complex balance between contradicting effects which occur simultaneously.