ReviewCancer-promoting mechanisms of tumor-associated neutrophils
Introduction
There is continuous crosstalk between cancer cells, stromal cells, and the immune system in the tumor microenvironment.1 Infiltrating neutrophils are found in many solid tumors, where they were classically considered indicative of a defensive immune response,2, 3, 4 however there is substantial evidence demonstrating neutrophils, via paracrine modulation, promote local tumor growth and play an active role in tumor progression to distant metastasis.5, 6, 7, 8, 9, 10
A recent study illustrates tumor cells induce unique phenotypic changes in peripheral blood monocytes into myeloid-derived suppressor cells (MDSC).10 These changes include expression of myeloid derived CD11b+, CD33+, CD66+.11, 12, 13 MDSCs have been shown to enter tumors and differentiate into tumor-associated neutrophils (TANs),14 which differ epigenetically and functionally from naïve, or classically defined, neutrophils. Transcriptome analysis between naïve neutrophils, MDSCs, and TANs shows that both TANs and MDSCs transcribe higher amounts of cytokine and chemokine mRNA (ICAM-1, CXCL-1 and 2, and CCL-17) than circulating neutrophils.15
TANs refer to a tumor-dependent, heterogeneous group of neutrophils which are sub-classified, similar to that of tumor-associated macrophages, based on their anti- or pro-tumor properties, known as N1 and N2, respectively.16 Recent experiments in murine lung cancer demonstrate that intra-tumor neutrophils initially display an anti-tumor phenotype- (N1) and as the tumor progresses TANs become distributed within the tumor and take on a pro-tumor phenotype (N2).17 The N1 TANs create inflammation by secreting cytokines (IL-1β, TNF-α, IL-6, and IL-12) and reactive oxygen species acting to damage (tumor) cells.18 However, these functions are down-regulated as the tumor progresses and the N2 phenotype become predominant.17
This review outlines this complex longitudinal interaction between TANs and tumor cells, including the role of TANs in local progression, intravasation, extravasation and macroscopic metastases.
Section snippets
Methods and materials
Literature searches were conducted on PubMed and Google Scholar included terms such as “Tumor-Associated Neutrophils AND Cancer,” “Angiogenesis AND Neutrophils AND Cancer.” Mechanistic drawings presented below were entirely created by these authors to illustrate the mechanisms reported in the literature search.
TANs effects on cellular proliferation
There is direct evidence demonstrating tumor cells modulate infiltrating neutrophils in the microenvironment. Neutrophils are recruited to the tumor microenvironment by genomic instability19 and tumor lysis, as well as chemokine and cytokine signaling. In particular, tumors expressing mutant K-ras induce IL-8 expression in infiltrating neutrophils via an NF-κB mechanism.20 Tumor derived IL-8 induces a signal cascade resulting in a reduced CD8+ and T-cell anti-tumor response. IL-8 signals PMN
Conclusions
Recent evidence suggests tumor cells induce epigenetic changes in local neutrophils to promote progression of the tumor. Tumor induced pro-cancer phenotype amongst cells of the innate immune system provides a new and cogent target for future cancer treatment. The ability of surgeons to direct regional therapies in combination with surgical resection promises a new era in the treatment of solid malignancies.
Conflict of interest statement
No financial interests or conflicts of interest to disclose.
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