title: The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis.
abstract: OBJECTIVE
  Our goals were to test the effect of acute lung infection on tumor metastasis and to investigate the underlying mechanisms.
  
  
  METHODS
  We combined bacteria-induced and lipopolysaccharide (LPS)-induced acute lung injury/inflammation (ALI) mouse models with mouse metastatic models to study the effect of acute inflammation on lung metastasis in mice. The mechanisms were investigated in ex vivo, in vitro, and in vivo studies.
  
  
  RESULTS
  Both bacteria- and LPS-induced ALI significantly enhanced lung metastasis of four tail vein-injected mouse tumor cell lines. Bacteria also enhanced lung metastasis when 4T1 cells were orthotopically injected. The bronchoalveolar lavage fluid (BALF) from LPS- or bacteria-injected mice stimulated migration of tumor cells. In vivo tracking of metastatic RM-9 cells showed that bacterial injection enhanced early dissemination of tumor cells to the lung. The majority of the BALF migratory activity could be blocked by AMD3100, a chemokine receptor 4 (CXCR4) inhibitor. All tested cell lines expressed CXCR4. The levels of extracellular ubiquitin, but not stromal cell-derived factor-1, in BALF were significantly increased by LPS. Ubiquitin was able to induce AMD3100-sensitive migration of tumor cells. Finally, the antibacterial agent amoxicillin and the CXCR4 inhibitor AMD3100 blocked the enhancement effect of bacterial infection on tumor metastasis.
  
  
  CONCLUSIONS
  Acute lung infection dramatically increased cancer cell homing to the lung and lung metastasis. This change may be due to an alteration of the lung microenvironment and preparation of a favorable metastatic "niche." This effect was seen in multiple cancer types and thus may have broad applications for cancer patients in prevention and/or treatment of metastasis.
authors.affiliation: Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Libo
authors.initials: L
authors.lastname: Yan
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Cai
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D000818:Animals; D001596:Benzylamines; D001992:Bronchoalveolar Lavage Fluid; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000080027:Cyclams; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D051379:Mice; D019718:Receptors, CXCR4 / Q000235:genetics*; D025801:Ubiquitin / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008070:Lipopolysaccharides; D019718:Receptors, CXCR4; D025801:Ubiquitin; C088327:plerixafor