FIBRIN DEPOSITION IN CANCER

血液凝固的局部和系统激活是 宿主对肿瘤生长的反应。凝血反应的产物， 尤其是纤维蛋白，可能在保护原发疾病中发挥重要作用 肿瘤不受宿主免疫系统效应臂的攻击，并可能 有利于转移瘤细胞的种植。与肿瘤相关 血栓栓塞症事件日益被认为是重要的 癌症并发症与癌症治疗。的长期目标是 本课题旨在了解心绞痛激活的发病机制。 癌症中的凝血；从而为设计提供有用的信息 癌症患者抗凝治疗的基本方法。我们 希望检验肿瘤相关巨噬细胞(TAMs)， 由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宿主 炎性细胞(TAMs)参与了能够激活血液的PCA 通过一条或多条途径凝结。纤维蛋白主要在 在(S)表面，而不是在肿瘤细胞上。权威的研究是 建议确定肿瘤细胞和TAMs之间的分子差异 它们各自合成、运输、结合和组装的能力 凝血因子和分泌PCA诱导的细胞因子-血管 渗透系数(VPF)。目前的实验计划强调了 前列腺癌组织因子(TF)及其配体因子VII的作用 CDNA探针、单抗和单特异性多克隆抗体以及生物素-- 与个体凝血相结合的标记氯甲酮连接肽 蛋白水解酶，我们将定位和原位表征关键的Pca(S)连接 人类肿瘤中的纤维蛋白沉积。将进行类似的研究 关于从SCID小鼠中恢复的人肿瘤移植瘤，以努力减少 将宿主和接受者免疫/炎症的贡献降至最低 细胞分化为PCa代。由于转铁蛋白是主要的肿瘤相关因子 PCA，提出了对人类转铁蛋白基因表达调控的研究。 细胞系对肿瘤衍生的细胞因子的反应，如VPF。

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.