Hemostatic factors, innate immunity and malignancy.
Genetics-based studies have established the critical importance of tumor cell-associated tissue factor, circulating and endothelial cell-associated regulators of thrombin function and multiple thrombin substrates in metastasis. There appear to be multiple pathways by which procoagulants influence tumor biology, but the capacity of hemostatic factors to regulate innate immune function is at least one emerging theme. Several reports have shown that the platelet/fibrin(ogen) axis supports metastasis by limiting natural killer cellmediated lysis of newly-localized micrometastases. Furthermore, there is increasingly compelling evidence that hemostatic and innate immune system interactions also support very early events in cancer development. Analyses of the role of fibrin(ogen) in inflammation-driven colon cancer established a major role for this provisional matrix protein in early tumor development. A seminal property of fibrin(ogen) driving tumor formation in this context is the capacity to support local leukocyte activation events through engagement of the leukocyte integrin α(M)β(2). More recent studies have also suggested that hemostatic factors can, in at least some settings, program the malignant phenotype in tumor cells. Platelet-derived TGF-β1 and other platelet products were reported to trigger a more invasive and prometastatic epithelial-mesenchymal-like transition in embolic tumor cells. These findings support the intriguing concept that tumor cell functional properties can continue to evolve, even beyond the primary tumor site, in response to tumor cell-hemostatic factor interactions in the bloodstream. Taken together, there is strong evidence that the hemostatic system plays a multifaceted role in cancer pathogenesis and that therapies targeting selected hemostatic factors may present a powerful means to impede tumor development and metastasis.
Cancer and Blood Diseases Institute, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA.
Jay L
JL
Degen
Joseph S
JS
Palumbo
D000818:Animals; D001779:Blood Coagulation Factors / Q000276:immunology*; D006487:Hemostasis / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology*
D001779:Blood Coagulation Factors