The Tyro3, Axl and Mer (TAM) receptor tyrosine kinases are activated by endogenous ligands, protein S1 (PROS1) and growth arrest-specific gene 6 (Gas6), and those have important effects on cell biology. These receptors (Rs) can be shad from the cell membrane and their soluble(s) forms can be found in plasma. We investigated the fluctuation and interactive role of sTAMRs and its ligands in patients with hepatocellular carcinoma (HCC), hepatitis groups, and healthy normal adult controls (NC). The measurement cases were 45 patients with HCC group (stage 1 in 4, stage 2 in 8, stage 3 in 16, and stage 4 in 17), 4 patients with fulminant hepatitis (FH), 14 patients with acute hepatitis (AH), 10 patients with chronic hepatitis (CH), 16 patients with liver cirrhosis (LC), and 20 NCs matched by age. Plasma levels of three sTAMRs and their ligands were measured by ELISA. In comparison with NCs, Gas6, des-γ-carboxy Gas6, and sTAMRs levels were significantly higher in HCC patients, but free PROS1 levels were significantly lower. The sTyro3 and sAxl levels peaked HCC stages 2 and 3 respectively, and gradually decreased afterwards while maintaining high levels. sMer levels increased with the progression of HCC. Gas6 and des-γ-carboxy Gas6 levels gradually increased, and PROS1 levels decreased with the progression of HCC. Gas6 levels were positively correlated with sAxl levels, whereas sMer levels were negatively correlated with free PROS1 levels. sTAMRs and Gas6 levels increased in parallel to the progression of HCC fibrosis. Through the progression of HCC, Axl played the major role in TAMRs activation. However, sTYro3 continued increasing rapidly from the early stage, and that of Mer increased throughout the progression. Roles of Axl may be changed in Mer, because des-γ-carboxy Gas6 levels increasing with Gas6 in the advanced stage of HCC cannot send a signal to Axl.
The purpose of this study was to determine the feasibility of a vaccine therapy using tumor necrosis factor (TNF) gene-transduced autologous tumor cells for the treatment of human gastrointestinal cancers, which tend to have lower immunogenicity than other cancers such as melanoma and renal cell carcinoma. We succeeded in establishing primary cultured tumor cells from 12/54 carcinomatous effusions (4 liver cancer patients, 5 gastric cancer patients, 1 pancreatic cancer patient, and 2 colon cancer patients) and in transducing the TNF gene to the tumor cells by using the retrovirus vector MFG-TNF. Even after irradiation, TNF production (0.3-3.5 U/ml per 10(6) cells per 72 hr) was confirmed for 10 of 12 transfectants, and the other two transduced cells were found to have approximately one TNF gene copy. In 7 of the 12 patients, the cytotoxic activity of killer cells to nontransduced autologous tumor cells incubated with these TNF gene transfectants was augmented. This activity was blocked with anti-HLA class I antibody or BrefeldinA (BFA), suggesting that the killer cells were cytotoxic T lymphocytes (CTL) and tumor antigens are presented with HLA class I molecules. Indeed, enhanced expression of HLA class I and/or ICAM-1 molecules on the surface of the TNF gene-transduced tumor cells were observed by fluorescence-activated cell sorting (FACS) analysis. Furthermore, natural killer (NK) and/or lymphokine-activated killer (LAK) activities determined by using K562 or Daudi cells as targets were also enhanced in some of these cases when they were incubated with TNF gene-transduced tumor cells. These findings indicate the feasibility of using TNF gene-transduced tumor cells as a vaccine in gastrointestinal cancer patients.
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