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.
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