Mechanisms linking hemostatic factors and malignancy

描述（由申请人提供）：本研究项目的长期目标 是了解关键止血因子在肿瘤发展中的作用， 转移当前的目标是使用可用的鼠标线， 纤维蛋白原、纤溶酶原和血小板功能的选择性缺陷， 确定这些止血因子的重要性和机制作用， 肿瘤生长和扩散。该项目的目标集中在以下方面 具体假设：i）止血因素是 自发转移和癌症存活; ii）肿瘤相关的 前纤维蛋白溶解剂和前凝血剂（例如，组织因子）改变 肿瘤细胞的转移潜力通过与以下偶联的机制 “宿主”的循环止血因子（例如，纤维蛋白原）; iii）血小板 激活通过增加肿瘤细胞增殖的机制支持肿瘤转移。 循环肿瘤栓塞的粘附和/或存活; iv）纤维蛋白原支持物 肿瘤细胞通过不依赖于纤维蛋白的机制转移 形成;和v）止血因子影响肿瘤的关键机制 细胞转移潜力是通过改变自然杀伤细胞（NK）的能力， 细胞识别和消除体内肿瘤栓塞。这些假设将是 通过对肿瘤细胞命运，实体瘤发展， 纤维蛋白原、纤溶酶原和Galphaq缺陷型的自发转移 小鼠（特定目的1和2）。此外，两者的机械作用 肿瘤中纤维蛋白原-血小板相互作用和纤维蛋白聚合物的形成 将通过在小鼠中进行全面的癌症研究来探索传播 表达突变形式的纤维蛋白原， 受体（α IIb β 3）结合基序或不能在体内结合（特异性 目标3）。最后，肿瘤细胞，止血因子， NK细胞在确定转移成功中的作用将通过详细的 肿瘤细胞的命运和转移的研究在小鼠中的单一和组合 止血因子和NK细胞功能缺陷（具体目标4）。的 拟议的研究将提供更详细的了解的影响， 止血因子对肿瘤生物学和扩散的影响，并可能导致 制定控制恶性疾病的新战略， 辅助治疗

DESCRIPTION (provided by applicant): The long-term aim of this research program is to understand the role of key hemostatic factors in tumor development and metastasis. The immediate objective is to use available mouse lines with selected defects in fibrinogen, plasminogen and platelet function to rigorously establish the importance and mechanistic role of these hemostatic factors in tumor growth and dissemination. The project aims center on the following specific hypotheses: i) hemostatic factors are important determinants of spontaneous metastasis and cancer survival; ii) tumor-associated profibrinolytic agents and procoagulants (e.g., tissue factor) alter the metastatic potential of tumor cells through mechanism(s) that are coupled to circulating hemostatic factors of the "host" (e.g., fibrinogen); iii) platelet activation supports tumor metastasis via a mechanism that increases the adherence and/or survival of circulating tumor emboli; iv) fibrinogen supports tumor cell metastasis through mechanism(s) that are independent of fibrin formation; and v) a key mechanism by which hemostatic factors influence tumor cell metastatic potential is by altering the ability of natural killer (NK) cells to recognize and eliminate tumor emboli in vivo. These hypotheses will be tested through detailed studies of tumor cell fate, solid tumor development, and spontaneous metastasis in fibrinogen-, plasminogen-, and Galphaq-deficient mice (Specific Aims 1 and 2). Further, the mechanistic role of both fibrinogen-platelet interaction and fibrin polymer formation in tumor dissemination will be explored by comprehensive cancer studies in mice expressing mutant forms of fibrinogen that either lack platelet integrin receptor (alphaIIbbeta3) binding motifs or cannot polymerize in vivo (Specific Aim 3). Finally, the relationship between tumor cells, hemostatic factors, and NK cells in determining metastatic success will be examined through detailed studies of tumor cell fate and metastasis in mice with single and combined defects in hemostatic factors and NK cell function (Specific Aim 4). The proposed studies will provide a more detailed understanding of the impact of hemostatic factors on tumor biology and dissemination, and could lead to the development of new strategies for controlling malignant disease based on adjunct therapies.