The development of novel treatment through the hepatocellular carcinoma (HCC) specific siginaling pathway and molecular based gene expression profiling for advanced HCC

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17390367
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Osaka University
• Principal Investigator: UMESHITA Koji Osaka University, Hospital, Assistant, 医学部附属病院, 助手 (60252649)
• Co-Investigator(Kenkyū-buntansha): NAGANO Hiroaki Osaka University, Graduate School of Medicine, lecturer, 医学系研究科, 講師 (10294050) ; DONO Keizo Osaka University, Graduate School of Medicine, lecturer, 医学系研究科, 講師 (60283769) ; YAMAMOTO Hirofumi Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (30322184) ; TAKEMASAO Ichiro Osaka University, Graduate School of Medicine, Assistant, 医学系研究科, 助手 (50379252) ; MONDEN Morito Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00127309)
• Project Period (FY): 2005 – 2006
• Keywords: hepatocellular carcinoma / advanced cancer / portal venous thrombus / IFN-α / chemotherapy / IFN-receptor / angiogenesis / Gene Expression Profiling

Research Abstract

1) The mechanism of the antitumor effect through the IFN-IFNAR signaling
The anti-tumor effect of IFN/5-FU combined therapy was significantly correlated with the strength of IFNAR expression, in the HCC cells in-vitro. In this mechanism, the methylation of IFNAR gene was significantly correlated with anti-tumor effect, among the several factors.
2) Anti tumor effect through the relationship between IFN and 5FU metabolism
In the anti-tumor effect of IFN and 5FU, IFN would induce the TS-1 inhibitory rate in 5FU metabolism.
3) Anti tumor effect through Fas/FasL
Among peripheral blood cells, NK cells were found to exert the cytotoxic effects on human hepatoma cells. In addition, the involvement of CTL system in the anti tumor effect was examined and confirmed in terms of the relationship of apoptosis in this study.
4) Anti tumor effect through the anti-angiogenic action
About the anti-angiogenic action of IFN, Ang-2 was the one of most important factor, among several anti-angiogenic molecules, TSP, Ang-1, VEGF, Tie2, HIF1-α.
5) The Gene Expression Profiling
Using the clinical samples treated by IFN-α and 5-FU, the gene expression profiling would be suggested to be useful for the prediction of the treatment efficacy at the over 85%.

Research Products

• [Journal Article] TGF-betal-induced cell growth arrest and partial differentiation is related to the suppression of Idl in human hepatoma cells. (2006)
  • Author(s): Damdinsuren B., Nagano H., Kondo M., Natsag J., Hanada H., Nakamura M., Wada H., Kato H., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Dono K., Monden M.
  • Journal Title: Oncol Rep 15(2) Pages: 401-408
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Angiogenesis in cholangiocellular carcinoma : Expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance. (2006)
  • Author(s): Tang D., Nagano H., Yamamoto H., Wada H., Nakamura M., Kondo M., Ota H., Yoshioka S., Kato H., Damdinsuren B., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Dono K., Wakasa K., Monden M.
  • Journal Title: Oncol Rep 15(3) Pages: 525-532
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-alpha and fluorouracil in vitro. (2006)
  • Author(s): Nakamura M, Nagano H, Noda T, Wada H, Ota H, Damdinsuren B, Marubashi S, Miyamoto A, Takeda Y, Doki Y, Umeshita K, Dono K, Sakon M, Monden M
  • Journal Title: Hepatology Research 35 Pages: 289-295
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical and pathological features of Allen's type C classification of resected combined hepatocellular and cholangiocarcinoma : a comparative study with hepatocellular carcinoma and cholangiocellular carcinom. (2006)
  • Author(s): Tang D., Nagano H., Nakamura M., Wada H., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Dono K., Monden M.
  • Journal Title: J Gastronitest Surg 2006 10(7) Pages: 987-998
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma : importance of angiopoietin-2 and hypoxia-induced factor-1 alpha. (2006)
  • Author(s): Wada H., Nagano H., Yamamoto H., Yang Y., Kondo M., Ota H., Nakamura M., Yoshioka S., Kato H., Damdinsuren B., Tang D., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Nakamori S., Sakon M., Dono K., Wakasa K., Monden M.
  • Journal Title: Liver International 26 Pages: 414-423
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Alpha-fetoprotein mRNA Detection in Peripheral Blood for Prediction of Hepatocellular Carcinoma Recurrence After Liver Transplantation. (2006)
  • Author(s): Marubashi S., Dono K., Sugita Y., Asaoka T., Hama N., Gotoh K., Miyamoto A., Takeda Y., Nagano H., Umeshita K., Monden M.
  • Journal Title: Transplant Proc 38(10) Pages: 3640-3642
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chmotherapy with the novel oral DPD-inhibiting chemotherapeutic drug S-1 and interferon-α. (2006)
  • Author(s): Nakamura M., Nagano H., Wada H., Noda T., Ota H., Damdinsuren B., Marubashi S., Miyamoto A., Takeda Y., Umeshita k., Dono K., Monden M.
  • Journal Title: J Gastroenterol 10(1007) Pages: 1120-1125
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TGF-betal-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells. (2006)
  • Author(s): Damdinsuren B., Nagano H., Kondo M., Natsag J., Hanada H., Nakamura M., Wada H., Kato H., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Dono K., Monden M.
  • Journal Title: Oncol Rep. 15(2) Pages: 401-408
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Angiogenesis in cholangiocellular carcinoma : Expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance. (2006)
  • Author(s): Tang D., Nagano H., Yamamoto H., Wada H., Nakamura M., Kondo M., Ota H., Yoshioka S., Kato H., Damdinsuren B., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Dono K., Wakasa K., Monden M.
  • Journal Title: Oncol Rep. 15(3) Pages: 525-532
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Vitamin K2 has growth inhibition effect against hepatocellular carcinoma cell lines but does not enhance anti-tumor effect of combination treatment of interferon-alpha and fluorouracil in vitro. (2006)
  • Author(s): Nakamura M, Nagano H, Noda T, Wada H, Ota H, Damdinsuren B, Marubashi S, Miyamoto A, Takeda Y, Doki Y, Umeshita K, Dono K, Sakon M, Monden M.
  • Journal Title: Hepatology Research. 35 Pages: 289-295
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical and pathological features of Allen's type C classification of resected combined hepatocellular and cholangiocarcinoma : a comparative study with hepatocellular carcinoma and cholangiocellular carcinom. (2006)
  • Author(s): Tang D., Nagano H., Nakamura M., Wada H., Marubashi S., Miyamoto A., Takeda Y., Umeshita K., Dono K., Monden M.
  • Journal Title: J Gastronitest Surg 10(7) Pages: 987-998
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Alpha-fetoprotein mRNA Detection in Peripheral Blood for Prediction of Hepatocellular Carcinoma Recurrence After Liver Transplantation. (2006)
  • Author(s): Marubashi S., Dono K., Sugita Y., Asaoka T., Hama N., Gotoh K., Miyamoto A., Takeda Y., Nagano H., Umeshita K., Monden M.
  • Journal Title: Transplant Proc. 38(10) Pages: 3640-3642
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chmotherapy with the novel oral DPD- inhibiting chemotherapeutic drug S-1 and interferon-α. (2006)
  • Author(s): Nakamura M., Nagano H., Wada H., Noda T., Ota H., Damdinsuren B., Marubashi S., Miyamoto A., Takeda Y., Umeshita k., Dono K., Monden M.
  • Journal Title: J Gastroenterol. 10(1007) Pages: 1120-1125
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association between recurrence of hepatocellular carcinoma and alpha-fetoprotein messenger RNA levels in peripheral blood. (2005)
  • Author(s): Morimoto O., Nagano H., Miyamoto A., Fujiwara Y., Kondo M., Yamamoto T., Ota H., Nakamura M., Wada H., Damdinsuren B., Marubashi S., Dono K., Umeshita K., Nakamori S., Sakon M., Monden M.
  • Journal Title: Surgery Today 35(12) Pages: 1033-1041
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association between recurrence of hepatocellular carcinoma and alpha-fetoprotein messenger RNA levels in peripheral blood. (2005)
  • Author(s): Morimoto O., Nagano H., Miyamoto A., Fujiwara Y., Kondo M., Yamamoto T., Ota H., Nakamura M., Wada H., Damdinsuren B., Marubashi S., Dono K., Umeshita K., Nakamori S., Sakon M., Monden M.
  • Journal Title: Surgery Today. 35(12) Pages: 1033-1041
  • Description: 「研究成果報告書概要(欧文)」より