Editors' ChoiceCancer Immunology

Neutrophils: Harbingers of metastasis?

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Science Translational Medicine  23 Dec 2015:
Vol. 7, Issue 319, pp. 319ec220
DOI: 10.1126/scitranslmed.aad9012

Neutrophils are the first responders to sites of injury and infection, but their role in cancer is poorly understood. Human tumors, often likened to “wounds that do not heal,” can display extensive neutrophil infiltration. These neutrophils are recruited through chemoattraction, adhesion, and transendothelial migration, analogous to tumor cell extravasation during metastasis. In some contexts, neutrophils suppress tumors through cytotoxic action or the recruitment of tumor-specific T cells. In others, neutrophils can promote tumor progression by sustaining inflammation.

Wculek and Malanchi showed that neutrophils can act as the primary driver of metastatic colonization in a mouse model of breast cancer. First, neutrophils infiltrated the lungs and secreted proinflammatory lipid mediators (leukotrienes) that stimulate adhesion, chemotaxis, and vascular permeability. In turn, tumor cells with leukotriene receptors were recruited to the lungs, a phenotype correlated with enhanced metastatic potential. This aggressive metastatic colonization was not observed in control experiments in which either neutrophils or leukotriene biosynthesis were genetically depleted. Inspired by these results, Wculek and Malanchi inhibited leukotriene production using the anti-asthma drug zileutin. Remarkably, zileutin treatment strongly suppressed lung metastases, although primary tumors and neutrophil counts remained largely unaffected.

Overall, this study elucidates how neutrophils can enhance metastasis by releasing inflammatory signals into the local microenvironment. These results suggest that leukotriene receptor expression and neutrophil counts may be useful clinical biomarkers. Moreover, the use of anti-inflammatory drugs to normalize the microenvironment could inhibit metastatic progression. Last, an intriguing therapeutic strategy is to reverse this mechanism—educate tumor-entrained neutrophils at the primary tumor to target metastases systemically.

S. K. Wculek, I. Malanchi, Neutrophils support lung colonization of metastasis-initating breast cancer cells. Nature 528, 413–417 (2015). [Abstract]

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