Journal
CANCER DISCOVERY
Volume 6, Issue 6, Pages 630-649Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-1157
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Funding
- Human Frontier Science Program [LT00728/2008-L]
- Charles King Trust Foundation
- Ludwig Fund for Cancer Research
- Cancer Research Institute Irvington Fellowship
- Leukemia and Lymphoma Society
- Sofie-Wallner-Preis
- Dr. Ernst und Anita Bauer-Stiftung
- NIH [P01 CA080111, U54 CA163109, R01 CA093678, R01 AI084880]
- Breast Cancer Research Foundation
- Ludwig Center for Molecular Oncology
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Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion-metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b(+)/Ly6G(+) neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1 beta and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells. SIGNIFICANCE: This study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion-metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells. (C) 2016 AACR.
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