The role of granulocyte colony‑stimulating factor in breast cancer development: A review

Abstract

Granulocyte-colony-stimulating factor (G-cSF) is a member of the hematopoietic growth factor family that primarily affects the neutrophil lineage. G-cSF serves as a powerful mobilizer of peripheral blood stem cells and recombinant human G-cSF (rhG-cSF) has been used to treat granulocytopenia and neutropenia after chemotherapy for cancer patients. However, recent studies have found that G-cSF plays an important role in cancer progression. G-cSF expression is increased in different types of cancer cells, such as lung cancer, gastric cancer, colorectal cancer, invasive bladder carcinoma, glioma and breast cancer. However, it is unclear whether treatment with G-cSF has an adverse effect. The current review provides an overview of G-cSF in malignant breast cancer development and the data presented in this review are expected to provide new ideas for cancer therapy. Contents 1. introduction 2. Structure of the G-cSF gene 3. regulation of G-cSF gene expression 4. The G-cSF receptor 5. G-cSF expression in breast cancer 6. direct effects of G-cSF on breast cancer 7. role of tumor microenvironment in the effect of G-cSF on breast cancer 8. conclusions

Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer

“…Neutrophils are continuously produced from bone marrow-derived pluripotent hematopoietic stem cells via the process of granulopoiesis in which G-CSF plays a key role not only by regulating the production of neutrophils, but also the activity of these cells [ 9 , 10 ]. G-CSF stimulates the proliferation of hematopoietic progenitors by accelerating their cell cycle rate, thus reducing the transit time through granulopoiesis, via enhancement of the transition of immature metamyelocytes into mature neutrophils and acceleration of their release into the circulation [ 10 ]. Apart from mediating the survival of neutrophils and their precursors, G-CSF also promotes the antimicrobial functions of mature neutrophils, such as phagocytosis, superoxide production and pathogen killing [ 11 ].…”

“…The G-CSFR is a single-chain membrane protein composed of extracellular, transmembrane and intracellular regions [ 10 , 19 ]. The large glycosylated extracellular region contains three distinct functional zones: an N-terminal immunoglobulin (Ig)-like domain, a cytokine receptor homology (CRH) domain and three fibronectin (FBN) type III domains [ 13 ].…”

“…Boxes 1 and 2 are required for activation of proliferation signals, while box 3 promotes the differentiation of myeloid progenitor cells [ 20 ]. In addition, phosphorylation of the four tyrosine residues at positions 704, 729, 744 and 764 is also a key event in intracellular signaling, resulting from phosphorylation of multiple SH2 (Src Homology 2)-containing signaling moieties [ 10 , 20 ].…”

“…In these settings, tumor-derived G-CSF induces accelerated myelopoiesis that results in a moderate and, in some instances, a profound leukocytosis that is associated with increased numbers of immature myeloid cells. These cells are found in the bone marrow, blood and spleen and their presence is predictive of a poor prognosis [ 10 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ].…”

“…The mechanisms by which G-CSF drives tumor progression vary according to the type of malignancy. For example, in the case of aggressive tumors with high-level expression of G-CSF/G-CSFR, such as breast cancer, gastric and colon cancers, squamous cell cancers of the head and neck and neuroblastoma, data derived from pre-clinical in vitro studies and animal models of tumorigenesis, as well as from histological/genotypic analysis of biopsy specimens from patients, have revealed the existence of autocrine mechanisms of tumor proliferation [ 10 , 80 , 85 , 86 , 87 ]. Intracellular signaling pathways involved in G-CSF/G-CSFR-activated tumor cell proliferation were, however, found to vary somewhat between tumor types.…”