Mechanisms linking hemostatic factors and malignancy

描述(申请人提供)：本研究计划的长期目标 是为了了解关键止血因素在肿瘤发生和发展中的作用 转移。直接的目标是使用可用的鼠标行 选择纤维蛋白原、纤溶酶原和血小板功能缺陷 确定这些止血因子的重要性和作用机制 肿瘤的生长和扩散。该项目的目标主要有以下几点 具体假设：i)止血因素是 自发转移与癌症存活率；ii)肿瘤相关 纤溶原药物和促凝血剂(如组织因子)改变 肿瘤细胞转移潜能的偶联机制(S) “宿主”的循环止血因子(如纤维蛋白原)；iii)血小板 激活支持肿瘤转移的机制是通过增加 循环肿瘤栓子的粘连和/或存活；iv)纤维蛋白原支持 不依赖纤维蛋白的肿瘤细胞转移机制(S) 形成；v)止血因素影响肿瘤的关键机制 细胞转移潜能是通过改变自然杀伤细胞(NK)的能力来实现的 细胞在体内识别和消除肿瘤栓子。这些假设将是 通过对肿瘤细胞命运的详细研究，实体肿瘤的发展， 纤维蛋白原、纤溶酶原和Galphaq缺乏的自发性转移 小鼠(特定目标1和2)。此外，两者的机械性作用 肿瘤中纤维蛋白原-血小板相互作用与纤维蛋白聚合物的形成 将通过在小鼠身上进行全面的癌症研究来探索传播 表达缺乏血小板整合素的纤维蛋白原突变形式 受体(AlphaIIbbeta3)结合基序或不能在体内聚合(特异性 目标3)。最后，肿瘤细胞、止血因子和 NK细胞在决定转移成功方面将通过详细的 单用和联合用药对小鼠肿瘤细胞去向和转移的影响 止血因子和NK细胞功能缺陷(特定目标4)。这个 拟议的研究将提供更详细的了解 止血因子对肿瘤生物学和播散的影响，并可能导致 新的恶性疾病控制策略的发展 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.