Neutrophil Degranulation, Plasticity, and Cancer Metastasis

An elevated neutrophil-to-lymphocyte ratio has become a prognostic indicator of poor overall survival in some cancers, and several inflammatory conditions have been identified as risk factors for cancer development. Several soluble neutrophil granule proteins released upon cell activation are associated with tumor progression and are considered as putative tumor biomarkers. Neutrophils physically interact with circulating tumor cells, facilitating their binding to the endothelium; they can promote tumor progression by inducing tumor cell proliferation, stimulating angiogenesis and matrix remodeling, and disabling T cell-dependent antitumor immunity. Neutrophil extracellular traps produced during inflammation may promote awakening of dormant tumor cells. Distinct neutrophil-like populations can affect tumor cells, but no available marker can distinguish these putative neutrophil-like populations. Differential mobilization of neutrophil cytoplasmic granules leads to the release of soluble granule contents and the incorporation of membrane granule proteins into cell surfaces, leading to changes in cellular functionality. This process might play a significant role in promoting the transport and extravasation of circulating tumor cells and thus facilitate their metastatic migration to distant sites. Neutrophils are the first responders to inflammation and infection. Recently, an elevated neutrophil-to-lymphocyte ratio has generally become a prognostic indicator of poor overall survival in cancer. Accordingly, heterogeneous ill-defined neutrophil-like populations have been increasingly recognized as important players in cancer development. In addition, neutrophil granule proteins released upon cell activation have been associated with tumor progression; this differential granule mobilization may allow neutrophils – and possibly associated cancer cells – to leave the bloodstream and enter inflamed/infected tissues. This review discusses and proposes how granule mobilization may facilitate neutrophil-mediated transport of cancer cells into different tissues as well as leading to different cellular phenotypes that underlie remarkable neutrophil plasticity. This concept might inform novel neutrophil-centered approaches to putative cancer therapies. Neutrophils are the first responders to inflammation and infection. Recently, an elevated neutrophil-to-lymphocyte ratio has generally become a prognostic indicator of poor overall survival in cancer. Accordingly, heterogeneous ill-defined neutrophil-like populations have been increasingly recognized as important players in cancer development. In addition, neutrophil granule proteins released upon cell activation have been associated with tumor progression; this differential granule mobilization may allow neutrophils – and possibly associated cancer cells – to leave the bloodstream and enter inflamed/infected tissues. This review discusses and proposes how granule mobilization may facilitate neutrophil-mediated transport of cancer cells into different tissues as well as leading to different cellular phenotypes that underlie remarkable neutrophil plasticity. This concept might inform novel neutrophil-centered approaches to putative cancer therapies. cell-mediated immune mechanism through which Fc receptor (a glycoprotein that binds to the Fc region of immunoglobulins)-bearing effector immune cells can recognize and kill antibody-coated target cells. ADCC effector cells include natural killer (NK) cells, monocytes, macrophages, neutrophils, eosinophils, and dendritic cells, and act through the release of cytotoxic granules or by the expression of cell death-inducing molecules. physiological process through which new blood vessels are created from pre-existing vasculature. intracellular self-degradative and regulated process through the formation of autophagosomes that delivers cytoplasmic constituents to the lysosome, allowing the orderly degradation and recycling of cellular components. Autophagy plays a major role in maintaining energy balance during development and in response to nutrient stress, and in removing misfolded or aggregated proteins, clearing damaged or unnecessary organelles, and eliminating intracellular pathogens. the observable characteristics or traits of a cell, including its particular morphology and function. dormant cells remain in a quiescent state (mitotic and growth arrest), survive in a slow-metabolic mode, and putatively reshape their genetic make-up until appropriate conditions are provided to begin proliferation again. a location tolerating antigens without eliciting an immune response. monitoring process of the immune system to detect and destroy neoplastic, infected, and other abnormal cells. unique protrusive and invasive dynamic actin-rich membrane structures; they degrade the extracellular matrix (ECM) via local deposition of concentrated proteases such as matrix metalloproteinases (MMPs); their formation is dependent on SNARE proteins. Invadopodia are found in cancer cells and are similar to the podosomes of normal cells. a vector-borne chronic infectious disease caused by many species of the protozoan Leishmania parasites that are transmitted by the bite of infected female phlebotomine sandflies. Three main forms of leishmaniases include cutaneous (skin ulcers), mucocutaneous (extensive mucosal ulceration and destruction in the skin, mouth, throat, or nose), and visceral (also known as kala-azar: enlarged spleen and liver, fatal if not treated). macrophages are not homogeneous and have been arbitrarily categorized as classically activated (M1, proinflammatory and killer, promoting antitumor inflammation) or alternatively activated (M2, anti-inflammatory and builder, supporting tumor growth). a distinct form of cell death characterized by the release of decondensed chromatin and granular contents into the extracellular space (NETs). networks of web-like structures of released chromatin filaments from neutrophils that are coated with histones, proteases, and granular and cytosolic proteins. These extracellular meshes entrap and kill invading microorganisms and provide scaffolds to promote high local concentrations of granule antimicrobial proteins. a process in which neutrophil cytoplasmic granules are mobilized to fuse with the cell membrane or phagosomal membrane, resulting in the exocytosis of soluble granule proteins or exposure of membrane granule proteins at the cell surface. cells displaying neutrophil-like morphology, sharing many protein markers of mature and immature neutrophils, and harboring immunosuppressive or proinflammatory functions. These are found in systemic inflammation, autoimmune diseases, and cancer; they include low-density neutrophils (LDNs), normal-density neutrophils (NDNs), myeloid-derived suppressor cells (MDSCs), and tumor-associated neutrophils (TANs) (Boxes Box 33 and Box 44). a trogocytosis (from Greek trogo, ‘to gnaw’)-related necrotic process of cell death described as a new cytotoxic effector mechanism in which neutrophils actively tear pieces from the target tumor cell membrane, gnawing holes in the cell surface until the tumor cell lyses.