Factor XIII Supports Metastatic Potential through a Mechanism Coupled to Natural Killer Cell Function.
Authors: Palumbo Joseph S. , Barney Kelley A. , Williams Elizabeth A. , Shaw Maureen A. , Mishra Anjali , Flick Matthew J. , Talmage Kathryn E. , Degen Jay L. 
Published: April 2020

Abstract
Interplay between the hemostatic and innate immune systems appears to be an important determinant of tumor metastasis. Studies of mice with selected hemostatic and/or immunological deficits have been particularly revealing, and indicate that platelets and fibrinogen support metastatic potential in part by impeding the clearance of newly formed micrometastases by natural killer (NK) cells. A key step in the formation of stable platelet/fibrin thrombi is the fXIII-mediated cross-linking of fibrin matrices. In order to examine the role of fXIII in tumor dissemination in detail, we studied tumor growth and metastasis in gene-targeted mice lacking the catalytic fXIII-A subunit (fXIII−/−). Comparative analyses of experimental lung metastases in immunocompetent fXIII−/− and wild-type mice showed that elimination of fXIII diminished the metastatic potential of both Lewis lung carcinoma (LLC) and B16-BL6 melanoma cells 5- to 10-fold. Loss of fXIII activity also significantly diminished tumor cell metastatic potential in spontaneous metastasis assays in which lung and liver lesions were quantified ∼2 weeks after resection of primary subcutaneous tumors. These differences were not the result of any genotype-dependent difference in tumor growth, as tumors transplanted into the dorsal subcutis of fXIII−/− and control mice grew at similar rates. In order to determine if fXIII was coupled to metastasis by a mechanism linked to NK cell function, we compared the early fate/survival of radiolabeled LLC cells in cohorts of fXIII−/− and wild-type mice pretreated with either an anti-asialo GM1 antibody known to deplete NK cells or control Ig. Here, the residual radiolabel present within lungs, blood and abdominal organs was measured 30 minutes or 26 hours after injection. Neither loss of fXIII nor NK cells had any impact on the initial localization of tumor cells within the lungs. The majority of the inoculum (∼90%) was present in the lungs 30 minutes after intravenous inoculation, with only scant amounts present in the other organs evaluated, regardless of mouse genotype or antibody treatment. Twenty-six hours after injection, fXIII deficiency resulted in a significant diminution in the apparent number of tumor cells remaining in the lungs in mice with intact NK cells. However, in mice immunologically depleted of NK cells, fXIII ceased to be a determinant of early tumor cell survival. These analyses identify fXIII as a significant determinant of metastatic potential and indicate that at least one mechanism whereby fXIII increases metastatic success is by impeding NK cell-mediated clearance of tumor cells. Given that these findings closely parallel previous observations made in fibrinogen-deficient mice, an attractive but still unproven model is that fXIII-mediated stabilization of fibrin/platelet aggregates associated with newly-formed micrometastases increases tumor cell survival in large part by limiting NK cell function. These studies also suggest that therapeutic strategies directed at fXIII might be useful in limiting malignant disease.