Factor XIII transglutaminase supports hematogenous tumor cell metastasis through a mechanism dependent on natural killer cell function.
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.
Palumbo
J S
JS
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
Barney
K A
KA
Blevins
E A
EA
Shaw
M A
MA
Mishra
A
A
Flick
M J
MJ
Kombrinck
K W
KW
Talmage
K E
KE
Souri
M
M
Ichinose
A
A
Degen
J L
JL
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
D005337:Fibrin; D005176:Factor XIII; D011503:Transglutaminases