This suggests that thrombin collaborates with OPN to induce the increased integrin-β1 expression.24 FAK plays critical roles in β1 integrin-dependent signaling,25 in survival signaling of circulating cells to avoid anoikis,26 and to form metastatic colonies.27 Disseminated cancer cells depend on survival signals to avoid rapid elimination by apoptosis.

Increasing evidence suggests that this pathway is abnormally Gefitinib regulated in HCC.28 To further elucidate the mechanism of these observations, we investigated the total and phosphorylated FAK levels. Treatment with thrombin significantly increased the phosphorylation of FAK in the OPN+ HCC cells; however, levels of total FAK remained unchanged. Moreover, thrombin-induced FAK phosphorylation was significantly inhibited NVP-AUY922 research buy by integrin-β1 neutralizing antibody. These data indicate that thrombin is able to regulate the integrin-β1/FAK pathway through the proteolytic modification

of OPN and affect the proliferation and adhesion abilities of HCC cells. In this study we not only provide convincing evidence that thrombin plays a crucial role in OPN-mediated function, but also an explanation as to why intravascular coagulation with generation of thrombosis has been observed in most patients with solid tumors.29, 30 A blood disorder involving hyperactivation of the coagulation system and formation of intravenous fibrin clots (thrombosis) can be the first manifestation of various tumors, including HCC.31 Meanwhile, some molecular targeted therapies such as sorafenib and sunitinib are associated with a significant increase in the risk of arterial thromboembolic events.32 The search for cancer-associated molecules

responsible for thrombosis could reveal targets to fight both the side effect as well as the primary disease. The treatment should start immediately after diagnosis and in conjunction Bacterial neuraminidase with molecular targeted therapies, especially sorafenib for those patients with advanced HCC.33 There are several thrombin inhibitors that are currently clinically available, including the broad-spectrum anticoagulants and the thrombin-specific inhibitors. Some of these agents have been demonstrated to have an inhibitory effect on metastatic behavior in experimental studies34; however, the main clinical applications of these agents thus far are for the treatment of disorders and complications, rather than for control of tumor metastasis.35 Despite these desired results, a number of unique challenges still exist for the treatment of cancer patients with antithrombotic agents, including suboptimal efficacy and high risk of bleeding using broad-spectrum agents, particularly for HCC patients, who often have a chronic hepatitis background.36 The use of more specific anticoagulants such as Argatroban, therefore, holds promise in terms of improved safety and efficacy.