Neutrophils Promote ALOX5-Dependent Breast Cancer Lung Metastasis

The initiation of metastasis requires a favorable microenvironment at the metastatic site, and targeting noncancer stromal cells may be an effective strategy to treat metastatic tumors. Wculek and Malanchi used a mouse model of metastatic mammary tumors to characterize leukocyte composition in metastases, and found that CD11b⁺Ly6G⁺ neutrophils were present at high frequency in lung metastases, but not primary tumors. Neutrophils infiltrated the metastatic sites before the tumor cells and promoted metastasis, without affecting the growth of primary tumors. In orthotopic mammary gland tumors, premetastatic neutrophil depletion with anti-Ly6G antibodies reduced the incidence of spontaneous lung metastases. Conditioned medium from premetastatic lung neutrophils (LuN) promoted tumor sphere growth in vitro and increased the metastatic initiation potential of cancer cells injected into Rag1-null mice. LuN media contained high levels of leukotrienes (LT) that are products of the arachidonate 5-lipoxygenase (ALOX5) enzyme, and LT stimulation was sufficient to promote sphere formation and enhance metastatic initiation potential. LT receptors were enriched on metastasis-initiating cells, which were increased in frequency in response to LT, further suggesting that neutrophils promote metastasis through leukotrienes. Genetic deficiency for Alox5 in the bone marrow did not alter the growth of the primary mammary tumors or accumulation of neutrophils in the lung; however, metastases were reduced. Conditioned medium from LuN derived from Alox5-null mice was not sufficient to promote metastasis, suggesting that ALOX5 is essential for the prometastatic effects of neutrophils. Furthermore, treatment with the ALOX5 inhibitor zileuton blocked LT production in vivo and reduced spontaneous metastasis in tumor-bearing mice without affecting lung neutrophil levels. Together, these data suggest that neutrophils promote tumor cell lung colonization and metastasis through ALOX5-dependent LT synthesis/release and that targeting LT/ALOX5 is a potential therapeutic approach to reduce tumor metastases.

Wculek SK, Malanchi I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 2015 Dec 9 [Epub ahead of print].