title: Premetastatic soil and prevention of breast cancer brain metastasis.
abstract: BACKGROUND
  As therapies for systemic cancer improve and patients survive longer, the risk for brain metastases increases. We evaluated whether immune mechanisms are involved in the development of brain metastasis.
  
  
  METHODS
  We conducted our studies using BALB/c mice bearing syngeneic 4T1 mammary adenocarcinoma cells in the mammary gland.
  
  
  RESULTS
  The brains of mice bearing 4T1 tumors at day 14 had no detectable metastatic tumor cells but presented with marked accumulation of bone marrow-derived CD11b(+)Gr1(+) myeloid cells, which express high levels of inflammatory chemokines S100A8 and S100A9. In vitro, S100A9 attracts 4T1 cells through Toll-like receptor 4 and CD11b(+)Gr1(+) myeloid cells through Toll-like receptor 4 and the receptor for advanced glycation end-products. Systemic treatment of 4T1-bearing mice with anti-Gr1 (RB6-8C5) monoclonal antibody reduces accumulation of CD11b(+)Gr1(+) myeloid cells in the day-14 premetastatic brain as well as subsequent brain metastasis of 4T1 cells detected on day 30. Furthermore, treatment of 4T1 tumor-bearing mice with the cyclooxygenase-2 inhibitor celecoxib or genetic disruption of cyclooxygenase-2 in 4T1 cells inhibits the inflammatory chemokines and infiltration of CD11b(+)Gr1(+) myeloid cells in the premetastatic brain and subsequent formation of brain metastasis.
  
  
  CONCLUSIONS
  Our results suggest that the primary tumor induces accumulation of CD11b(+)Gr1(+) myeloid cells in the brain to form "premetastatic soil" and inflammation mediators, such as S100A9, that attract additional myeloid cells as well as metastatic tumor cells. Celecoxib and anti-Gr1 treatment may be useful for blockade of these processes, thereby preventing brain metastasis in patients with breast cancer.
authors.affiliation: Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Akemi
authors.initials: A
authors.lastname: Kosaka
authors.forename: Maki
authors.initials: M
authors.lastname: Ikeura
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Wendy
authors.initials: W
authors.lastname: Fellows-Mayle
authors.forename: Linda A
authors.initials: LA
authors.lastname: Snyder
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism; D000068579:Celecoxib; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D039481:CD11b Antigen; D040502:Calgranulin B; D052246:Cyclooxygenase 2 Inhibitors; C503133:Gr-1 protein, mouse; D018836:Inflammation Mediators; D011720:Pyrazoles; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C576329:S100A9 protein, mouse; D013449:Sulfonamides; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib
keywords: CCL2; S100A8/A9; brain metastasis; breast cancer; myeloid-derived suppressor cells; prostaglandin-E2