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. Nevertheless, the role of neutrophils in tumors, both at the primary and secondary sites, remains controversial, with some studies reporting their anti-tumor functions. This review will focus on the data demonstrating a role for neutrophils in both tumor growth and metastasis and will attempt to clarify the discrepancies in the literature.
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.
Evidence is mounting for a contribution of neutrophils to breast cancer progression. Herein we discuss recent clinical and experimental evidence that G‐CSF and/or neutrophils promote metastasis. 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.
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. Herein we discuss the most recent data relating to the effect of G-CSF on the major immune populations, exclusively in the context of cancer. Recent publications have drawn attention to the other tumour-promoting effects of G-CSF on myeloid cells, including NETosis, promotion of cancer stemness and skewed differentiation of bone marrow progenitors towards myelopoiesis. Although G-CSF is safely and commonly used as a supportive therapy to prevent or treat chemotherapy-associated neutropenia in cancer patients, we also discuss the potential impacts of G-CSF on other anti-cancer treatments. Importantly, considerations for immune checkpoint blockade are highlighted, as many publications report a T cell suppressive effect of G-CSF that may diminish the effectiveness of this immunotherapy.
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. We show that mouse mammary tumour cells preferentially home to a pre-existing metaphyseal domain enriched for type H vessels. Metastatic lesion outgrowth rapidly remodelled the local vasculature through extensive sprouting to establish a tumour-supportive microenvironment. The evolution of this tumour microenvironment reflects direct remodelling of the vascular endothelium through tumour-derived granulocyte-colony stimulating factor (G-CSF) in a hematopoietic cell-independent manner. Therapeutic targeting of the metastatic niche by blocking G-CSF receptor inhibited pathological blood vessel remodelling and reduced bone metastasis burden. These findings elucidate a mechanism of 'host' microenvironment hijacking by mammary tumour cells to subvert the local microvasculature to form a specialised, pro-tumorigenic niche.
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. While the CSF-1R is the sole receptor for CSF-1, an alternative functional ligand for the receptor, interleukin-34 (IL-34), was recently identified. CSF-1-induced CSF-1R activation triggers autophosphorylation of several intracellular tyrosine residues, leading to initiation of an array of phosphotyrosine-based signaling cascades that mediate the wide variety of cellular responses to CSF-1. Dissecting the contributions of the different phosphorylated tyrosine motifs of the receptor to downstream signaling events in macrophages is not only important for our understanding of CSF-1R function, but also for the development of inhibitors to treat diseases where infiltrating macrophages contribute to their progression. This review will outline our current understanding of the CSF-1/CSF-1R signaling axis and describe how a novel macrophage cell line system, which allows examination of CSF-1R signaling in a mature macrophage context, is helping us to tease apart the diverse signaling pathways initiated by CSF-1R activation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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. Consequently, G-CSF has been used to support patients undergoing chemotherapy who would otherwise require dose reduction due to neutropenia. Over the past 10–15 years it has become increasingly apparent, in preclinical tumour growth and metastasis models, that G-CSF can support tumour progression by mobilization of tumour-associated neutrophils which consequently promote tumour dissemination and metastasis. With the increasing use of G-CSF in the clinic, it is pertinent to ask if there is any evidence of a similar promotion of tumour progression in patients. Here, we have reviewed the preclinical and clinical data on the potential contribution of G-CSF to tumour progression. We conclude that, whilst the evidence for a promotion of metastasis is strong in preclinical models and that limited data indicate that high serum G-CSF levels in patients are associated with poorer prognosis, no studies published so far have revealed evidence of increased tumour progression associated with supportive G-CSF use during chemotherapy in patients. Analysis of G-CSF receptor positive cohorts within supportive trials, as well as studies of the role of G-CSF blockade in appropriate tumours in the absence of chemotherapy could yield clinically translatable findings.
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. Here we show that pY721‐based signaling is necessary for CSF‐1‐stimulated PtdIns(3,4,5)P production. While primary bone marrow‐derived macrophages and the immortalized bone marrow‐derived macrophage cell line M−/−.WT express all three class IA PI3K isoforms, p110δ predominates in the cell line. Treatment with p110δ‐specific inhibitors demonstrates that the hematopoietically enriched isoform, p110δ, mediates CSF‐1‐regulated spreading and invasion in macrophages. Thus GS‐1101, a potent and selective p110δ inhibitor, may have therapeutic potential by targeting the infiltrative capacity of tumor‐associated macrophages that is critical for their enhancement of tumor invasion and metastasis.
SFKs are required for CSF‐1R signaling to motility and invasion, with different expression profiles in human and mouse macrophages.
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. We report a comprehensive analysis of individual Src family kinase expression in macrophage cell lines and primary macrophages and demonstrate colony‐stimulating factor‐1–induced changes in Src family kinase subcellular localization, which provides clues to their distinct and redundant functions in macrophages. Moreover, expression of individual Src family kinases is both species specific and dependent on colony‐stimulating factor‐1–induced macrophage differentiation. Hck associated with the activated colony‐stimulating factor‐1 receptor, whereas Lyn associated with the receptor in a constitutive manner. Consistent with this, inhibitor studies revealed that Src family kinases were important for both colony‐stimulating factor‐1 receptor activation and colony‐stimulating factor‐1–induced macrophage spreading, motility, and invasion. Distinct colony‐stimulating factor‐1–induced changes in the subcellular localization of individual SFKs suggest specific roles for these Src family kinases in the macrophage response to colony‐stimulating factor‐1.
Abstract
Dormancy is a major clinical problem in breast cancer. Although the five-year survival rate is high, 15% of the patients will relapse. Cancer cells that disseminate from the tumor (DTCs) can ...enter a dormant state that allows survival in the face of standard-of-care therapies. These DTCs are the source of cancer recurrence. Currently little is known about the molecular drivers that initiate dormancy. MYC is a well-known oncogene that is aberrantly regulated in many cancers, including breast cancer. It is involved in proliferation, tumorigenesis, and diapause. We propose that MYC is also a master regulator of dormancy. To investigate its role in dormancy, we generated cell lines with regulatable levels of MYC expression. Using an in vitro dormancy assay, we have shown that reduced MYC levels induce dormancy in otherwise aggressive cell lines. In mice bearing human breast tumors, the loss of MYC activity following primary tumor removal greatly reduces the extent of metastasis. The DTCs in lungs, livers, spine, and femurs are maintained as small clusters with few cells, while control mice have many and large metastases. MYC reduction maintains the DTCs in this dormant-like state for at least 32 days after primary tumor removal. Importantly, when MYC levels are restored, the DTCs exit the dormant state, and overt metastasis ensues. Currently, we are comparing the transcriptomes of dormant DTCs to actively growing metastatic cells to generate a MYC-driven dormancy signature that will elucidate potential dormancy genes to target therapeutically in the clinic. To complement our genetic studies, we are investigating pharmacological suppression of MYC activity. The bromodomain inhibitor I-BET151 reduces MYC protein levels and induces dormancy in our in vitro assay. Mice treated with I-BET151 after primary tumor removal had significantly reduced levels of metastasis in lung, liver, and spine when compared to their non-treated counterparts. Testing of this compound in an immune-competent preclinical model is currently underway. Our data imply that MYC is an important regulator of dormancy in breast cancer. Our future experiments will elucidate dormancy genes as potential targets that could lead to life-saving therapies in the clinic.
Citation Format: Charlotte Roelofs, Kellie A. Mouchemore, Anannya Chakrabarti, Richard P. Redvers, Robin L. Anderson. MYC as a master regulator of dormancy in triple negative breast cancer abstract. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A010.
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. Here we show that pY721-based signaling is necessary for CSF-1-stimulated PtdIns(3,4,5)P production. While primary bone marrow-derived macrophages and the immortalized bone marrow-derived macrophage cell line M-/-.WT express all three class IA PI3K isoforms, p110delta predominates in the cell line. Treatment with p110delta-specific inhibitors demonstrates that the hematopoietically enriched isoform, p110delta, mediates CSF-1-regulated spreading and invasion in macrophages. Thus GS-1101, a potent and selective p110delta inhibitor, may have therapeutic potential by targeting the infiltrative capacity of tumor-associated macrophages that is critical for their enhancement of tumor invasion and metastasis.
PDF
