title: Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function.
abstract: BACKGROUND
  Multiple studies suggest that the hemostatic and innate immune systems functionally cooperate in establishing the fraction of tumor cells that successfully form metastases. In particular, platelets and fibrinogen have been shown to support metastatic potential through a mechanism coupled to natural killer (NK) cell function. As the transglutaminase that ultimately stabilizes platelet/fibrin thrombi through the covalent crosslinking of fibrin, factor (F) XIII is another thrombin substrate that is likely to support hematogenous metastasis.
  
  
  OBJECTIVE
  Directly define the role of FXIII in tumor growth, tumor stroma formation, and metastasis.
  
  
  METHODS
  Tumor growth and metastatic potential were quantitatively and qualitatively evaluated in wild-type mice and gene-targeted mice lacking the catalytic FXIII-A subunit.
  
  
  RESULTS
  Loss of FXIIIa function significantly diminished hematogenous metastatic potential in both experimental and spontaneous metastasis assays in immunocompetent mice. However, FXIII was not required for the growth of established tumors or tumor stroma formation. Rather, detailed analyses of the early fate of circulating tumor cells revealed that FXIII supports the early survival of micrometastases by a mechanism linked to NK cell function.
  
  
  CONCLUSIONS
  Factor XIII is a significant determinant of metastatic potential and supports metastasis by impeding NK cell-mediated clearance of tumor cells. Given that these findings parallel previous observations in fibrinogen-deficient mice, an attractive hypothesis is that FXIII-mediated stabilization of fibrin/platelet thrombi associated with newly formed micrometastases increases the fraction of tumor cells capable of evading NK cell-mediated lysis.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. joe.palumbo@cchmc.org
authors.forename: J S
authors.initials: JS
authors.lastname: Palumbo
authors.forename: K A
authors.initials: KA
authors.lastname: Barney
authors.forename: E A
authors.initials: EA
authors.lastname: Blevins
authors.forename: M A
authors.initials: MA
authors.lastname: Shaw
authors.forename: A
authors.initials: A
authors.lastname: Mishra
authors.forename: M J
authors.initials: MJ
authors.lastname: Flick
authors.forename: K W
authors.initials: KW
authors.lastname: Kombrinck
authors.forename: K E
authors.initials: KE
authors.lastname: Talmage
authors.forename: M
authors.initials: M
authors.lastname: Souri
authors.forename: A
authors.initials: A
authors.lastname: Ichinose
authors.forename: J L
authors.initials: JL
authors.lastname: Degen
mesh_terms: D000818:Animals; D001792:Blood Platelets; D005176:Factor XIII / Q000378:metabolism / Q000502:physiology*; D005337:Fibrin; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000473:pathology*; D009369:Neoplasms / Q000209:etiology*; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D013927:Thrombosis; D011503:Transglutaminases / Q000378:metabolism*; D019139:Tumor Escape / Q000502:physiology
chemical_list: D005337:Fibrin; D005176:Factor XIII; D011503:Transglutaminases