Neutrophil-derived granule cargoes: paving the way for tumor growth and progression

Abstract

Neutrophils are the key cells of our innate immune system mediating host defense via a range of effector functions including phagocytosis, degranulation, and NETosis. For this, they employ an arsenal of anti-microbial cargoes packed in their readily mobilizable granule subsets. Notably, the release of granule content is tightly regulated; however, under certain circumstances, their unregulated release can aggravate tissue damage and could be detrimental to the host. Several constituents of neutrophil granules have also been associated with various inflammatory diseases including cancer. In cancer setting, their excessive release may modulate tissue microenvironment which ultimately leads the way for tumor initiation, growth and metastasis. Neutrophils actively infiltrate within tumor tissues, wherein they show diverse phenotypic and functional heterogeneity. While most studies are focused at understanding the phenotypic heterogeneity of neutrophils, their functional heterogeneity, much of which is likely orchestrated by their granule cargoes, is beginning to emerge. Therefore, a better understanding of neutrophil granules and their cargoes will not only shed light on their diverse role in cancer but will also reveal them as novel therapeutic targets. This review provides an overview on existing knowledge of neutrophil granules and detailed insight into the pathological relevance of their cargoes in cancer. In addition, we also discuss the therapeutic approach for targeting neutrophils or their microenvironment in disease setting that will pave the way forward for future research.

Neutrophil-to-Lymphocyte Ratio as a Factor Predicting Radiotherapy Induced Oral Mucositis in Head Neck Cancer Patients Treated with Radiotherapy

“…The physiological function of neutrophils is very complex. They work in many mechanisms and have an impact on numerous metabolic processes [ 22 , 32 , 36 , 37 , 38 ]. In turn, the development of OM in HNC patients is based on over 14 previously described canonical pathways [ 39 ].…”

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

“…It is also involved in the pathogenesis of various infectious and non-infectious diseases, such as autoimmune, cardiovascular, thrombotic, and neoplastic diseases, etc. [2,[10][11][12][13]. It is known that DNA must be removed from the system rapidly, since it may stimulate an inflammatory response, as observed in the suggested relationship between the presence of extracellular DNA and several autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), as well as HIV infection, cardiovascular diseases, and neoplasms [14][15][16][17].…”

“…In tumors, it has been found that NETs-derived granule proteins may contribute to the migration of tumor cells from the primary site to other sites, favoring the formation of metastases [11,12,91]. The type of disease associated with NETs is related to the trap formation site and their degradation mechanisms [24].…”

Hyperactive Neutrophils Infiltrate Vital Organs of Tumor Bearing Host and Contribute to Gradual Systemic Deterioration With Tumor Progression

“…MMPs play a critical role in tumor progression by facilitating tumor cell invasion and show broad catalytic activity against components of ECM (Roy, Yang et al 2009). Neutrophils are known to be the major source of MMPs (specifically, MMP-8 and -9) (Fligiel, Standiford et al 2006, Rawat, Syeda et al 2021.…”

“…However, under certain circumstances, unregulated release of these effector molecules can aggravate tissue damage and could be detrimental to the host (Pham 2008). In cancer setting, their excessive release can modulate tissue microenvironment (Coffelt, Wellenstein et al 2016) and ultimately lead the way for tumor initiation, growth and metastasis (Rawat, Syeda et al 2021). Their aberrant activation or persistence at inflammatory site is also associated with various inflammatory disorders ranging from chronic obstructive pulmonary disease (COPD) (Meijer, Rijkers et al 2013), neutrophilic asthma (Chung 2016), rheumatoid arthritis (Apel, Zychlinsky et al 2018) to the recent pandemic COVID-19 (Ackermann, Anders et al 2021).…”