Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis.

Bone marrow is a preferred metastatic site for multiple solid tumours and is associated with poor prognosis and significant morbidity. Accumulating evidence indicates that cancer cells colonise specialised niches within the bone marrow to support their long-term propagation, but the precise location and mechanisms that mediate niche interactions are unknown. Using breast cancer as a model of solid tumour metastasis to the bone marrow, we applied large-scale quantitative three-dimensional imaging to characterise temporal changes in the bone marrow microenvironment during disease progression.

Immunomodulatory effects of G-CSF in cancer: Therapeutic implications.

Numerous preclinical studies have reported a pro-tumour role for granulocyte colony-stimulating factor (G-CSF) that is predominantly mediated by neutrophils and MDSCs, the major G-CSF receptor expressing populations. In the presence of G-CSF (either tumour-derived or exogenous) these myeloid populations commonly exhibit a T cell suppressive phenotype. However, the direct effects of this cytokine on other immune lineages, such as T and NK cells, are not as well established.

The dark side of granulocyte-colony stimulating factor: a supportive therapy with potential to promote tumour progression.

Granulocyte-colony stimulating factor (G-CSF) is one of several cytokines that can expand and mobilize haematopoietic precursor cells from bone marrow. In particular, G-CSF mobilizes neutrophils when the host is challenged by infection or tissue damage. Severe neutropenia, or febrile neutropenia is a life-threatening event that can be mitigated by administration of G-CSF.

Neutrophils, G-CSF and their contribution to breast cancer metastasis.

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.

Src family kinase expression and subcellular localization in macrophages: implications for their role in CSF-1-induced macrophage migration.

A major role of colony-stimulating factor-1 is to stimulate the differentiation of mononuclear phagocytic lineage cells into adherent, motile, mature macrophages. The colony-stimulating factor-1 receptor transduces colony-stimulating factor-1 signaling, and we have shown previously that phosphatidylinositol 3-kinase p110δ is a critical mediator of colony-stimulating factor-1-stimulated motility through the colony-stimulating factor-1 receptor pY721 motif. Src family kinases are also implicated in the regulation of macrophage motility and in colony-stimulating factor-1 receptor signaling, although functional redundancy of the multiple SFKs expressed in macrophages makes it challenging to delineate their specific functions.

Neutrophils: important contributors to tumor progression and metastasis.

The presence of neutrophils in tumors has traditionally been considered to be indicative of a failed immune response against cancers. However, there is now evidence showing that neutrophils can promote tumor growth, and increasingly, the data support an active role for neutrophils in tumor progression to distant metastasis. Neutrophils have been implicated in promoting metastasis in cancer patients, where neutrophil numbers and neutrophil-related factors and functions have been associated with progressive disease.

Specific inhibition of PI3K p110δ inhibits CSF-1-induced macrophage spreading and invasive capacity.

Colony stimulating factor-1 (CSF-1) stimulates mononuclear phagocytic cell survival, growth and differentiation into macrophages through activation and autophosphorylation of the CSF-1 receptor (CSF-1R). We have previously demonstrated that CSF-1-induced phosphorylation of Y721 (pY721) in the receptor kinase insert triggers its association with the p85 regulatory subunit of phosphoinositide 3'-kinase (PI3K). Binding of p85 PI3K to the CSF-1R pY721 motif activates the associated p110 PI3K catalytic subunit and stimulates spreading and motility in macrophages and enhancement of tumor cell invasion.

CSF-1 signaling in macrophages: pleiotrophy through phosphotyrosine-based signaling pathways.

Colony stimulating factor-1 (CSF-1, also known as macrophage-colony stimulating factor, M-CSF) has long been known as the primary growth factor regulating survival, proliferation and differentiation of macrophages and other mononuclear phagocytic (MNP) lineage cells. CSF-1 was subsequently identified as a monocyte/macrophage chemokine, a capacity now recognized to be integral to many of the deleterious as well as positive roles of macrophages in development, homeostasis and disease. The pleiotrophic actions of CSF-1 are all transduced by its high affinity receptor, the CSF-1R, a receptor tyrosine kinase (RTK) and the cellular homologue of the v-fms oncoprotein.