STUDIES OF FIBRIN DEPOSITION IN CANCER

癌症中纤维蛋白沉积的研究

• 批准号: 3165771
• 负责人: FREDERICK R. RICKLES
• 金额: $ 20.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165771
• 关键词: blood coagulation; coagulation factor VII; cytotoxicity; fibrin; human subject; in situ hybridization; laboratory mouse; macrophage; metastasis; molecular site; monoclonal antibody; neoplasm /cancer immunology; neoplastic cell; thrombin; thromboplastin; tissue /cell culture

Local and systemic activation of blood coagulations is an integral part of the host response to tumor growth. Products of clotting reactions, particularly fibrin, may play an important role in protecting primary tumors from attack by the effector arm of the host immune system and may be advantageous for the seeding of metastatic tumor cells. Tumor-related thromboembolic events are increasingly recognized as important complications of cancer and cancer therapy. The long-term objective of this project is to understand the pathogenesis of the activation of clotting in cancer; thereby to provide useful information for the design of rationale approaches to anticoagulation therapy of cancer patients. We wish to test the hypothesis that tumor-associated macrophages (TAMs), activated locally by tumor cell cytokines to express procoagulant activity (PCA), are central to the pathophysiology of these events. Evidence exists that both tumor cells and tumor-associated, host inflammatory cells (TAMs) can contribute PCA capable of activating blood clotting by one or more pathways. Fibrin is detected principally on the surface of TAM(s) rather than on tumor cells. Definitive studies are proposed to determine molecular differences between tumor cells and TAMs in their respective ability to synthesize, transport, bind and assemble clotting factors and to secrete the PCA-inducing cytokine, vascular permeability factor (VPF). The present experimental plan emphasized the role for the PCA tissue factor (TF) and its ligand, factor VII. Utilizing cDNA probes, monoclonal and monospecific polyclonal antibodies and biotin- labeled chloromethylketone-linked peptides bound to individual clotting proteases, we will localize and characterize in situ the key PCA(s) linked to fibrin deposition in human tumors. Similar studies will be performed on human tumor xenografts recovered from SCID mice, in an effort to reduce to a minimum the contribution of host and recipient immune/inflammatory cells to PCA generation. Since TF is the predominant tumor-associated PCA, studies are proposed of the regulation of TF gene expression in human cell lines in response to tumor-derived cytokines, like VPF.

血液凝固的局部和全身激活是血液凝固的组成部分。 宿主对肿瘤生长的反应 凝血反应的产物， 特别是纤维蛋白，可能在保护原发性 肿瘤免受宿主免疫系统的效应臂的攻击， 有利于转移性肿瘤细胞的接种。 肿瘤相关 血栓栓塞事件越来越被认为是重要的 癌症并发症和癌症治疗。 的长期目标 该项目旨在了解激活的发病机制， 癌症中凝结;从而为设计提供有用的信息 癌症患者抗凝治疗的合理方法。 我们 希望检验肿瘤相关巨噬细胞（TAM）， 被肿瘤细胞因子局部激活以表达促凝血活性 (PCA)是这些事件的病理生理学的核心。 有证据表明，肿瘤细胞和肿瘤相关的宿主 炎性细胞（TAM）可以提供能够活血的PCA 通过一种或多种途径凝血。 主要在 TAM的表面而不是肿瘤细胞上。 连续性研究是 提出确定肿瘤细胞和TAM之间的分子差异 在它们各自的合成、运输、结合和组装能力中 凝血因子和分泌PCA诱导细胞因子，血管 渗透系数（VPF）。 目前的实验计划强调， PCA组织因子（TF）及其配体因子VII的作用。 利用 cDNA探针、单克隆和单特异性多克隆抗体和生物素- 标记的氯甲基酮连接肽与个体凝血结合 蛋白酶，我们将在原位定位和表征关键PCA（S）连接 人类肿瘤中的纤维蛋白沉积。 将进行类似的研究 在从SCID小鼠中回收的人肿瘤异种移植物上， 将宿主和受体免疫/炎症的贡献降至最低 细胞到PCA生成。 由于TF是主要的肿瘤相关性 PCA，研究TF基因表达的调控在人类 细胞系对肿瘤源性细胞因子如VPF的反应。