title: Neutrophils support lung colonization of metastasis-initiating breast cancer cells.
abstract: Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.
authors.affiliation: The Francis Crick Institute, Lincolns Inn Fields Laboratories, 44 Lincolns Inn Fields, London WC2A 3LY, UK.
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Wculek
authors.affiliation: The Francis Crick Institute, Lincolns Inn Fields Laboratories, 44 Lincolns Inn Fields, London WC2A 3LY, UK.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Malanchi
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology*; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D001094:Arachidonate 5-Lipoxygenase