title: Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice.
abstract: Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both protumor and antitumor effects. Here, neutrophils promoted the growth of hepatic metastases, given that depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization. Metastasis-associated neutrophils expressed substantially more fibroblast growth factor 2 (FGF2) than naïve neutrophils, indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density, and branching.
  
  
  
  Here, we show, using FGF2 as an example, that identification of factors responsible for the protumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. (Hepatology 2017;65:1920-1935).
authors.affiliation: Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, United Kingdom.|CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Alex N
authors.initials: AN
authors.lastname: Gordon-Weeks
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Su Y
authors.initials: SY
authors.lastname: Lim
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Arseniy E
authors.initials: AE
authors.lastname: Yuzhalin
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Keaton
authors.initials: K
authors.lastname: Jones
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Markelc
authors.affiliation: Galaxy Biotech, LLC, Sunnyvale, CA.
authors.forename: K Jin
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Jon N
authors.initials: JN
authors.lastname: Buzzelli
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Cao
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Sean
authors.initials: S
authors.lastname: Smart
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
authors.forename: Ruth
authors.initials: R
authors.lastname: Muschel
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001707:Biopsy, Needle; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000473:pathology; D011897:Random Allocation; D018709:Statistics, Nonparametric; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D016222:Fibroblast Growth Factor 2