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Summary. Background: Activation of the complement system has been implicated in tumor growth. The antifibrinolytic protein, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), can modulate the activation of the complement system by inactivating the anaphylatoxins C3a and C5a. The apolipoprotein-E (ApoE) genotype has been associated with carcinogenesis. Objective: The aim of this study was to evaluate whether TAFIa can affect the development of cancer in the ApoE-deficient mouse model. Methods: TAFI and ApoE double-knockout mice were generated. A group of mice was treated with the diabetogenic and carcinogenic compound streptozotocin (stz). Mice treated with saline, single knockout mice and wild-type (wt) mice served as controls. Results: Six months after treatment with stz, mice were sacrificed. Hepatic tumors were found in male double-knockout mice treated with stz but none was found in control animals that were not treated with stz or in single knockout of ApoE or wt animals. There was no significant difference in coagulation system activation between the groups of mice. The plasma concentrations of C5a, factor D and transforming growth factor-b1 were increased in TAFI/ApoE double-deficient mice treated with stz compared with the mice of the same genotype treated with saline. Conclusion: Apo-E deficiency alone was not associated with tumors but the lack of TAFI appears to make the mice permissive for tumor formation in ApoE mice.

Abstract. The risk factors for the development of hepatocellular carcinoma (HCC) in patients who have achieved a long-term sustained viral response (SVR) to interferon (IFN) are not fully understood. This study aimed to investigate the characteristics of patients who developed HCC after 10 years of achieving SVR. We retrospectively studied 5 patients with HCC which developed more than 10 years after the termination of IFN therapy. The clinical characteristics at the induction of IFN therapy were male gender, a mean age of 51.6±9.1 years, while 2 patients were moderate alcohol consumers. None of the 5 patients were positive for either HBs Ag or anti-HBc Ab. A histological examination at the initial IFN therapy showed the activity scores to be A2 in all cases, and the fibrosis scores at least F2. The clinical parameters at the diagnosis of HCC included fluctuating transaminase levels in all cases. These levels scarcely fell below the upper limits even after SVR was achieved. In 3 patients, liver tissues were obtained at the treatment of HCC. These tissues showed marked improvement in both activities and fibroses, but severe steatosis in 1 patient. To conclude, chronic hepatitis C patients who respond to IFN therapy should undergo long-term follow-up, even after the eradication of HCV, with special attention particularly to patients who had elevated transaminase levels and steatosis. IntroductionHepatocellular carcinoma (HCC) is the major cause of cancerrelated death in Japan. Approximately 70-80% of HCCs in Japanese patients are associated with hepatitis C virus (HCV) infection (1). HCV causes chronic infection in more than 70% of cases, and liver disease gradually progresses to liver cirrhosis and finally to HCC.Interferon (IFN) has been used for the treatment of chronic hepatitis C (CHC) patients. Many investigators have reported that IFN treatment is effective in the reduction of the serum alanine amino transferase (ALT) level, eliminating HCV RNA from the circulation and improving liver histology in CHC patients (2-6). In certain patients, IFN therapy normalizes the serum ALT levels and leads to sustained eradication of HCV. These patients are commonly referred to as having achieved a sustained viral response (SVR) (7), and it has been noted that the cumulative incidence of HCC is significantly lower in SVR patients than in those with a non-response (NR) to IFN therapy (8,9), suggesting that the success of treatment for HCV infection is expected to significantly reduce the risk of developing HCC.However, the development of HCC among CHC patients with SVR to IFN therapy has been reported (10-16). In most cases, HCCs occurred within 5 years after the termination of IFN treatment. The risk factors for developing HCC after achieving SVR were suggested in these reports; however, the associated significant factors remain unknown. Moreover, the risk factors for the development of HCC in patients who have achieved SVR for more than 10 years are not fully understood. Therefore, it remains undetermined which patient g...

Abstract

Abstract. Toll-like receptor 3 (TLR3) is a pattern-recognizing receptor that is involved in immune signaling and plays a crucial role in survival by being able to recognize various viral components including double-stranded RNA (dsRNA). TLR3 expression and function in cancer cells are not well understood. We investigated the expression of TLR3 in hepatocellular carcinoma (HCC) cells and the function of TLR3 signaling by stimulation and transfection with polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA. TLR3 mRNA was expressed in HCC tissues as well as in non-tumor tissues. Positive immunohistochemical staining for TLR3 was observed in 52.7% of HCC tissues, and in HCC cells we found both membranous and cytoplasmic expression of TLR3. While cell surface stimulation of TLR3 with Poly I:C did not affect cell viability, it did activate NF-κB levels. In contrast, cytoplasmic stimulation with transfected Poly I:C significantly induced apoptosis accompanied by the down-regulation of anti-apoptotic protein. Transfected Poly I:C also synergistically augmented TRAIL-induced apoptosis, but only with low levels of transfected Poly I:C was IFN-ß production not observed. In conclusion, our results indicate that TLR3 expression in HCC plays an important role with regard to cell survival and proapoptotic activity. Endogenously expressed TLR3 may provide new clinical prospects for TLR3 agonists as cytotoxic agents in HCC.