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.

Nature doi: 10.1038/nature16140

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