title: Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells.
abstract: 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 IL1β 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.
  
  
  
  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. Cancer Discov; 6(6); 630-49. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Asaf
authors.initials: A
authors.lastname: Spiegel
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Mary W
authors.initials: MW
authors.lastname: Brooks
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Samin
authors.initials: S
authors.lastname: Houshyar
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, California.
authors.forename: Michele
authors.initials: M
authors.lastname: Ardolino
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fessler
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Krall
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Jasmine
authors.initials: J
authors.lastname: DeCock
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Ioannis K
authors.initials: IK
authors.lastname: Zervantonakis
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, California.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Iannello
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Virna
authors.initials: V
authors.lastname: Cortez-Retamozo
authors.affiliation: Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Kamm
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mikael J
authors.initials: MJ
authors.lastname: Pittet
authors.affiliation: Department of Molecular and Cell Biology and Cancer Research Laboratory, Division of Immunology, University of California at Berkeley, Berkeley, California.
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Massachusetts Institute of Technology Ludwig Center for Molecular Oncology, Cambridge, Massachusetts. weinberg@wi.mit.edu.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers; D002277:Carcinoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D007113:Immunity, Innate; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D010641:Phenotype
chemical_list: D015415:Biomarkers; D016207:Cytokines; D020782:Matrix Metalloproteinases