Palumbo J S, Barney K A, Blevins E A, Shaw M A, Mishra A, Flick M J, Kombrinck K W, Talmage K E, Souri M, Ichinose A, Degen J L
Division of Hematology/Oncology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
J Thromb Haemost. 2008 May;6(5):812-9. doi: 10.1111/j.1538-7836.2008.02938.x. Epub 2008 Feb 25.
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.
Directly define the role of FXIII in tumor growth, tumor stroma formation, and metastasis.
Tumor growth and metastatic potential were quantitatively and qualitatively evaluated in wild-type mice and gene-targeted mice lacking the catalytic FXIII-A subunit.
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.
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.
多项研究表明，止血和先天免疫系统在确定成功形成转移灶的肿瘤细胞比例方面存在功能协作。特别是，血小板和纤维蛋白原已被证明通过与自然杀伤（NK）细胞功能相关的机制来支持转移潜能。作为通过纤维蛋白的共价交联最终稳定血小板/纤维蛋白血栓的转谷氨酰胺酶，因子（F）XIII是另一种可能支持血行转移的凝血酶底物。
直接确定FXIII在肿瘤生长、肿瘤基质形成和转移中的作用。
在野生型小鼠和缺乏催化性FXIII - A亚基的基因靶向小鼠中，对肿瘤生长和转移潜能进行定量和定性评估。
在免疫活性小鼠的实验性和自发性转移试验中，FXIIIa功能的丧失显著降低了血行转移潜能。然而，FXIII对于已建立肿瘤的生长或肿瘤基质形成并非必需。相反，对循环肿瘤细胞早期命运的详细分析表明，FXIII通过与NK细胞功能相关的机制支持微转移灶的早期存活。
因子XIII是转移潜能的重要决定因素，通过阻碍NK细胞介导的肿瘤细胞清除来支持转移。鉴于这些发现与先前在纤维蛋白原缺陷小鼠中的观察结果相似，一个有吸引力的假设是，FXIII介导的与新形成的微转移灶相关的纤维蛋白/血小板血栓的稳定增加了能够逃避NK细胞介导裂解的肿瘤细胞比例。
