Neutrophil-Mediated Survival and Extravasation of Disseminated Carcinoma Cells

Distant site metastases represent the leading cause of cancer-associated mortality. As the biological complexity of tumor growth and metastasis is explored more fully, it has become apparent that key aspects of tumor biology can only be explained by a detailed understanding of the contributions to tumor growth by host cell components. While the role of local immune-neoplastic interactions in the microenvironment has been the subject of intensive investigations, relatively little is known about the function of circulating immune cells on the more dynamic and transient phases of the later steps of the invasion-metastasis cascade following entrance of cancer cells into the general circulation. Here we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that G-CSF released by primary tumors enhances the mobilization of CD11b⁺/Ly6G⁺ neutrophils into the circulation. The newly mobilized neutrophils proceed to enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL-1β and matrix metalloproteinases. These results identify a network of host cell interactions between innate immune cells, tumor cells and endothelial cells, and positions neutrophils at the core of this network. This dynamic crosstalk regulates the intravascular stages of the invasion-metastasis cascade - intraluminal survival following metastatic dissemination and subsequent extravasation, i.e., entrance of cancer cells into the parenchyma of target tissues.