Mechanisms linking hemostatic factors and malignancy

止血因素与恶性肿瘤的联系机制

• 批准号: 6623049
• 负责人: JAY L DEGEN
• 金额: $ 35.83万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623049
• 关键词: CHO cells; blood coagulation; carcinoma; disease /disorder model; fibrinogen; gene targeting; genetically modified animals; hemostatics; integrins; laboratory mouse; lung neoplasms; melanoma; metastasis; mutant; natural killer cells; neoplastic cell; neoplastic growth; plasminogen; platelet activation; protein structure function; thromboplastin

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.

描述（由申请人提供）：该研究计划的长期目标 是了解关键止血因素在肿瘤发育中的作用和 转移。直接目的是将可用的鼠标线与 纤维蛋白原，纤溶酶原和血小板功能的选定缺陷至严格 确定这些止血因素在 肿瘤的生长和传播。该项目目标中心以下 特定的假设：i）止血因素是重要的决定因素 自发转移和癌症存活； ii）肿瘤相关 纤维蛋白水解剂和凝聚剂（例如，组织因子）改变了 肿瘤细胞通过机制的转移潜力，该机制偶联 “宿主”的循环止血因子（例如纤维蛋白原）； iii）血小板 激活通过一种增加的机制支持肿瘤转移 循环肿瘤栓子的依从性和/或存活； iv）纤维蛋白原支持 通过独立于纤维蛋白的机制肿瘤细胞转移 形成； v）止血因素会影响肿瘤的关键机制 细胞转移电位是通过改变自然杀手（NK）的能力 细胞以识别和消除体内肿瘤栓子。这些假设将是 通过对肿瘤细胞命运，实体瘤发展的详细研究测试， 和纤维蛋白原，纤溶酶原和galphaq缺陷的自发转移 小鼠（特定目标1和2）。此外，两者的机械作用 肿瘤中的纤维蛋白原 - 血小板相互作用和纤维蛋白聚合物形成 小鼠的全面癌症研究将探索传播 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（特定 目标3）。最后，肿瘤细胞，止血因素和 NK细胞确定转移性成功，将通过详细研究检查 单一和合并的小鼠中肿瘤细胞命运和转移的研究 止血因子和NK细胞功能的缺陷（特定目标4）。这 拟议的研究将对对的影响有更详细的了解 肿瘤生物学和传播的止血因素，可能导致 制定基于控制恶性疾病的新策略 辅助疗法。