Abstract
Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.
Highlights
Proteinase 53.1(.PTRh3e)N, weuhtriocphhiilsMeaxcp-1reInstseerdactoionntwhiethnTeuumtroor pIChAilMs,c1an interact with Receptor for advanced glycation end products (RAGE) on tumor cells and induce proliTfheeraretiaorne osof mtheesttuumdieosr tchealtlsh. ave shown an interaction between neutrophil Mac-1 (CD11b/CD18; Complement Receptor 3) and ICAM-1 (CD54) on certain tumor cells, which facilitated the metastatic seeding of the tumor cells in the liver and the lungs [54,239,240]
The two neutrophil phenotypes coexist in cancer together with immunosuppressive granulocyte myeloid-derived suppressor cells (G-MDSCs) at various ratios that often change during tumor progression from a prominent anti-tumor phenotype to a predominant protumor phenotype
This continuum of neutrophil activities discourages the use of the “N1” and “N2” terminology that defines two quite different subpopulations
Summary
Neutrophils are short-lived white blood cells of the innate immune system that are continuously replenished by newly differentiated cells in the bone-marrow. The neutrophils are differentiated in the bone-marrow from a common myeloid progenitor (CMP) through a common granulocyte-monocyte progenitor (GMP) This is followed by several stages: myeloblasts, promyelocytes, myelocytes, metamyelocytes ( called banded neutrophils or immature neutrophils) and mature neutrophils [1,2,3,4]. The differential release of the various granules of the neutrophils may contribute to the neutrophil heterogeneity, versatility and plasticity observed under various pathophysiological conditions [7,8] This may explain why the premature neutrophils released to the circulation exhibit different properties than the mature neutrophils, and why the neutrophils, during their short lifespan, exhibit different traits depending on the stimuli perceived and their stage of differentiation. Exposure to different combinations of cytokines and chemokines modulates the activation state of the mature neutrophils and normal and emergency granulopoiesis [9,10]
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