The Role Of Thrombin As A Potent Proinflammatory Signaling Molecule In Cancer Pathogenesis

Blood coagulation and inflammation are closely intertwined pathways. Thrombin, a multifunctionalserine protease in plasma, regulates numerous pathophysiological processes related to coagulationand inflammation. Thrombin through activation of protease-activated receptors (PARs) initiatesproinflammatory signaling responses in in vitro and in vivo systems. Proinflammatory signalingfunction of thrombin increases release of proinflammatory cytokines and chemokines, triggersvascular permeability, promotes leukocytes migration, and induces adhesion moleculesexpression. Thrombin as a potent signaling molecule is strongly implicated in a number ofproinflammatory disorders including severe sepsis, neurodegenerative disorders, cardiovasculardisease, and of special interest in this review cancer. Tumor cells express high level of tissue factor(TF) which upon binding to factor VIIa triggers more thrombin generation in the tumormicroenvironment. Thrombin contributes to the malignant phenotype by enhancing tumor celladhesive and metastatic properties. Thrombin activation of PARs leads to upregulation of variousadhesion molecules, such as the GPIIb-IIIa integrin, P-selectin, and CD40 ligand, these adhesionmolecules are required for tumor cells migration and adhesion between tumor cells, platelets,endothelial cells, and the extracellular matrix which lead to tumor progression(8).Thrombin alsocontributes to the malignant phenotype by induction of various growth factors, chemokines, andcytokines secretion that promote the stimulation of proliferation, differentiation and migration ofcancer cells. Moreover, thrombin is involved in angiogenesis by inducing inflammatory cytokinesthat could enhance the angiogenic process in human malignancies. Taken together, Thrombinthrough increasing vascular permeability, platelet activation and overexpression of adhesionmolecules, proinflammatory cytokines, chemokines and proangiogenic factors regulates tumor cellproliferation, differentiation, migration and angiogenesis. A deeper understanding of the majorsignaling pathways involved in thrombin-induced – inflammation could thus lead to the design ofagent to regulate the proinflammatory signaling function of thrombin and have great clinicalsignificance in terms of the treatment of cancer. This review summarizes the acquired knowledgeon mechanisms of thrombin-mediated proinflammatory responses in cancer for a betterunderstanding and hence a better management of this disease.