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

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Abstract

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.

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Abbreviations

G-CSF:

Granulocyte-colony stimulating factor

CSF-1:

Colony stimulating factor-1

GM-CSF:

Granulocyte macrophage colony stimulating factor

DFS:

Disease-free survival

PFS:

Progression-free survival

RFS:

Recurrence-free survival

BCSS:

Breast cancer specific survival

OS:

Overall survival

MDSC:

Myeloid derived suppressor cells

NET:

Neutrophil extracellular trap

NLR:

Neutrophil to lymphocyte ratio

CIN:

Chemotherapy induced neutropenia

RDI:

Relative dose intensity

RR:

Rate ratio

HR:

Hazard ratio

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Acknowledgements

The authors wish to acknowledge grant support from the National Health and Medical Research Council (NHMRC) (APP1080560 – RLA and JAH) and from the National Breast Cancer Foundation (NBCF) of Australia (PS-15-022 – RLA and JAH). Fellowship support from the NBCF (RLA) and scholarship support from Monash University (KAM) are also acknowledged. Olivia Newton-John Cancer Research Institute acknowledges the support of Operational Infrastructure Program of Victorian Government.

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Authors and Affiliations

  1. Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, VIC, 3084, Australia

    Belinda Yeo & Robin L. Anderson

  2. Austin Health, Heidelberg, VIC, 3084, Australia

    Belinda Yeo

  3. Fiona Stanley Hospital, Perth, WA, Australia

    Andrew D. Redfern

  4. Peter MacCallum Cancer Centre, Parkville, VIC, Australia

    Kellie A. Mouchemore

  5. Department of Biochemistry & Molecular Biology, Monash University, Clayton, VIC, Australia

    Kellie A. Mouchemore

  6. Arthritis and Inflammation Research Centre, Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC, Australia

    John A. Hamilton

  7. Australian Institute for Musculoskeletal Science (AIMSS), The University of Melbourne and Western Health, St. Albans, VIC, Australia

    John A. Hamilton

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  1. Belinda Yeo
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  2. Andrew D. Redfern
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  3. Kellie A. Mouchemore
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  4. John A. Hamilton
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  5. Robin L. Anderson
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Correspondence to Robin L. Anderson.

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Belinda Yeo and Andrew D. Redfern are joint first authors.

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Yeo, B., Redfern, A.D., Mouchemore, K.A. et al. The dark side of granulocyte-colony stimulating factor: a supportive therapy with potential to promote tumour progression. Clin Exp Metastasis 35, 255–267 (2018). https://doi.org/10.1007/s10585-018-9917-7

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  • DOI: https://doi.org/10.1007/s10585-018-9917-7

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