The thrombin-inflammation axis in cancer progression

The last half century of cancer research has seen an explosion in our understanding of the complex interplay between cancer cells and host-derived factors critical for cancer progression. Two important host-derived arms that are part of this complex interplay are the inflammatory immune compartment and the hemostatic system. Chronic pathological inflammation is a major factor in the development of multiple common malignancies, including adenocarcinomas of the colon, pancreas, prostate and breast. Hemostatic system components have also been shown to promote cancer progression in multiple contexts. What is only recently been recognized is the link between inflammation and hemostasis in cancer progression. The hemostatic and inflammatory innate immune systems co-evolved to deal with many of the same challenges, including trauma, infections, and thermal/chemical injuries. Their co-evolution necessarily led to bidirectional cross-talk whereby inflammatory cells can activate and alter hemostasis, and hemostatic system components serve as important regulators of inflammatory processes. This cross-talk is critical for the maintenance of vascular integrity, host defense, and wound healing. However, in the context of malignancy, the interplay of these integrated host systems has the capacity to promote multiple stages of malignancy, including tumorigenesis, tumor growth and metastatic dissemination. This review focuses on the interplay of inflammatory cells with the thrombin-fibrinogen axis and protease-activated receptor-1 in cancer pathobiology. Dissecting the mechanisms by which the inflammatory and hemostatic systems cooperatively promote cancer progression will fill in critical knowledge gaps in our understanding of malignancy, and also likely reveal novel therapeutic targets to treat and/or prevent cancer.