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Building the route to metastasis
Infection triggers the release of the phospholipid S1P, which stimulates macrophages to launch a proinflammatory response, including secretion of the protein lipocalin 2 (LCN2). Dying tumor cells also release S1P. Using human primary cells and mouse models, Jung et al. discovered that a multicellular signaling circuit involving the release of S1P from dying breast tumor cells to stimulate release of LCN2 from tumor-associated macrophages stimulated the release of the lymphangiogenic factor VEGFC from lymphatic endothelial cells, thus promoting the growth of lymphatic vessels in the tumor microenvironment. Inhibiting the pathway suppressed lymphangiogenesis and metastasis in mice. The findings reveal not only therapeutic targets but also a way that therapy-induced tumor cell death and viral or bacterial infection could prime the microenvironment for metastasis (see also the Focus by Rodvold and Zanetti).
Abstract
Tumor cell–derived factors skew macrophages toward a tumor-supporting phenotype associated with the secretion of protumorigenic mediators. Apoptosing tumor cells release sphingosine 1-phosphate (S1P), which stimulates the production of lipocalin 2 (LCN2) in tumor-associated macrophages and is associated with tumor metastasis. We explored the mechanism by which S1P induces LCN2 in macrophages and investigated how this contributed to tumor growth and metastasis. Knockdown of S1P receptor 1 (S1PR1) in primary human macrophages and experiments with bone marrow–derived macrophages from S1PR1-deficient mice showed that S1P signaled through S1PR1 to induce LCN2 expression. The LCN2 promoter contains a consensus sequence for signal transducer and activator of transcription 3 (STAT3), and deletion of the STAT3 recognition sequence reduced expression of an LCN2-controlled reporter gene. Conditioned medium from coculture experiments indicated that the release of LCN2 from macrophages induced tube formation and proliferation in cultures of primary human lymphatic endothelial cells in a manner dependent on the kinase PI3K and subsequent induction of the growth factor VEGFC, which functioned as an autocrine signal stimulating the receptor VEGFR3. Knockout of Lcn2 attenuated tumor-associated lymphangiogenesis and breast tumor metastasis both in the breast cancer model MMTV-PyMT mice and in mice bearing orthotopic wild-type tumors. Our findings indicate that macrophages respond to dying tumor cells by producing signals that promote lymphangiogenesis, which enables metastasis.
