Neutrophils, G‐CSF and their contribution to breast cancer metastasis

Abstract

Evidence is mounting for a role for neutrophils in breast cancer progression to metastasis. However, the role of G‐CSF in neutrophil biology in a cancer setting remains to be defined. Herein we discuss the most recent clinical and experimental evidence for neutrophils and G‐CSF in the promotion of metastasis, demonstrating a potential mechanistic link between them. Understanding this link is imperative both for the development of diagnostic tests and for therapies targeting neutrophils to improve the treatment of breast cancer patients with or at risk of developing metastatic disease. As a high neutrophil‐to‐lymphocyte ratio in patients predicts poor outcome, while mild neutropenia predicts an improved outcome, we urge caution in the use of G‐CSF in neutrophil recovery following chemotherapy as there is increasing evidence in preclinical models that G‐CSF can promote metastasis.

Cell autonomous versus systemic Akt isoform deletions uncovered new roles for Akt1 and Akt2 in breast cancer

“…In addition, neutrophils form neutrophil extracellular traps (NETs) that stimulate migration and invasion and trap natural killer cells 25 . The pro-metastatic role of neutrophils was also recognized in human cancer patients, and a high NLR is associated with a poor prognosis 14 . The neutrophils derived from tumor-bearing mice or from cancer patients are distinct from normal neutrophils, as tumor-associated neutrophils lack immunosuppressive activity and have a higher migration capacity 26 .…”

“…The neutrophils derived from tumor-bearing mice or from cancer patients are distinct from normal neutrophils, as tumor-associated neutrophils lack immunosuppressive activity and have a higher migration capacity 26 . Cancer cells promote the survival and mobilization of neutrophils by secreting G-CSF 14, 27 . We showed that at least in vitro Akt1, and not Akt2, is required for the G-CSF-induced survival of neutrophils derived from tumor-bearing mice.…”

“…4c). Neutrophils play a pro-metastatic role in breast cancer 14, 15 , and a high neutrophil to lymphocyte ratio (NLR) is associated with worse overall survival and disease-free survival 16 . Consistent with the reported pro-metastatic role of neutrophils that provide a niche for the metastatic cells in the lungs, we found that neutrophils within lung metastases and primary tumors express, in addition to high Ly6g and Cxrc2, which are known neutrophils markers, relatively high levels of S100a8 , S100a9 , MMP8 , MMP9 , Bv8 / Prok2 and vascular endothelial growth factor ( Vegfa ), which promote invasion and migration (Fig.…”

“…To understand the mechanism by which Akt1 affects tumor-associated neutrophils, we isolated neutrophils from tumor-bearing mice and exposed these cells to granulocyte colony stimulating factor (G-CSF) in vitro. G-CSF was shown to promote the survival of neutrophils and is required for the mobilization of tumor-associated neutrophils 14 . As shown in Fig.…”

Cancer-associated hypersialylated MUC1 drives the differentiation of monocytes into macrophages with a pathogenic phenotype

“…Neutrophil function. Neutrophils have been shown to contribute to breast cancer metastasis [29][30][31] . A number of chemokines such as CXCL5, CXCL8 and CCL24 32,33 that are differentially expressed in MUC1-ST macrophages compared to M-CSF macrophages are involved in neutrophil recruitment (figure 4a).…”