Mechanisms linking hemostatic factors and malignancy

点击翻译按钮获取中文摘要

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.