2002 Fiscal Year Annual Research Report

低酸素適反応を標的とした膵癌治療の開発

Research Project

Project/Area Number	14370170
Research Institution	Hokkaido University
Principal Investigator	小林正伸北海道大学, 遺伝子病制御研究所, 助教授 (80241321)
Co-Investigator(Kenkyū-buntansha)	小林隆彦北海道大学, 医学部附属病院, 講師 (80333607) 進藤正信北海道大学, 大学院・歯学研究科, 助教授 (20162802)
Keywords	Hypoxin / HIF-1 / アポトーシス / 血管新生 / 転移 / AMF / adrenomedullin
Research Abstract	正常酸素分圧下でHIF-1αを発現している大部分の膵癌細胞株がアポトーシス抵抗性であることを見出しており(Cancer Res.,2001)、膵癌細胞が他の固形癌と比較して低酸素や低栄養に低抗性であり、血管が少ない状況でも増殖できることを示している。そこで申請者は、膵癌が隣接臓器などへの浸潤頻度が高く、早期から肝転移を認めるなど、浸潤・転移能の高い原因を明らかにするためにDNA microarrayにて低酸素下で発現亢進する転移関連遺伝子を探索した。その結果、Liottaらによって見出されいたautocrine motility factor (AMF)やMMP-9、5T4 onco-fetal proteinが低酸素下で発現亢進する遺伝子であることを見出した。これらの遺伝子のうちautocrine motility factorについては、各種の癌細胞において低酸素下で誘導されそれらの癌細胞の運動能を亢進させることを報告した(Br J cancer,2002)。またdominant negative HIF-1α遺伝子導入膵癌細胞株ではAMFの発現亢進が完全に抑制され、運動能も抑制された。これらの結果はdominant negative HIF-1αの有用性を示唆する。また申請者は、低酸素下で誘導される新しい血管新生因子adrenomedullinを見出し、adrenomedullin antagonistにて腫瘍増殖を完全に抑制できることを報告した(Oncogene,2003)。これらの事実は、膵癌細胞のアポトーシス耐性や転移においてHIF-1蛋白が重要な役割を果たしていることを示唆する。またHIF-1の機能を抑制することによって癌組織の増殖や転移を抑制し、抗癌剤の効果増強が得られる可能性が考えられた。

Research Products

(12 results)

All Other

All Publications (12 results)

[Publications] Suzuki S: "Autocrine production of epithelial cell-derived neutrophil attractant-78 (ENA-78) induced by G-CSF in neutrophils"Blood. 99. 1863-1865 (2002)
[Publications] Niizeki H: "Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells"Br J Cancer. 86. 1914-1919 (2002)
[Publications] 小林正伸: "HIF-1(解説)"生化学. 74. 492 (2002)
[Publications] Wang J: "MyD88 is involved in signaling pathway for Taxol-induced apoptosis and TNF-α expression in human myelomonocytic cells"Br J. Haematol.. 118. 638-645 (2002)
[Publications] Zhao W: "Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II"Cancer Immunol. Immunother.. 51. 381-388 (2002)
[Publications] Masauji N: "Mean fluorescence intensity (MFI) of CD11b on CD34-positive (CD34+) cells derived from granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood (PB) correlate conversely with the total amount of harvested CD34+ cells"Ann Heamatol.. 81. 183-184 (2002)
[Publications] Suzuki S: "Autocrine production of epithelial cell-derived neutrophil attractant-78 (ENA-78) induced by G-CSF in neutrophils"Blood. 99. 1863-1865 (2002)
[Publications] Niizeki H: "Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells"Br J Cancer. 86. 1914-1919 (2002)
[Publications] 小林正伸: "HIF-1(解説)"生化学. 74. 492 (2002)
[Publications] Wang J: "MyD88 is involved in signaling pathway for Taxol-induced apoptosis and TNF-α expression in human myelomonocytic cells"Br J. Haematol. 118. 638-645 (2002)
[Publications] Zhao W: "Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II"Cancer Immunol. Immunother.. 51. 381-388 (2002)
[Publications] Masauji N: "Mean fluorescence intensity (MFI) of CD11b on CD34-positive (CD34+) cells derived from granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood (PB) correlate conversely with the total amount of harvested CD34+ cells"Ann Heamatol.. 81. 483-484 (2002)

2002 Fiscal Year Annual Research Report

低酸素適反応を標的とした膵癌治療の開発

Principal Investigator

小林 正伸 北海道大学, 遺伝子病制御研究所, 助教授 (80241321)

Research Products

[Publications] Suzuki S: "Autocrine production of epithelial cell-derived neutrophil attractant-78 (ENA-78) induced by G-CSF in neutrophils"Blood. 99. 1863-1865 (2002)

[Publications] Niizeki H: "Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells"Br J Cancer. 86. 1914-1919 (2002)

[Publications] 小林正伸: "HIF-1(解説)"生化学. 74. 492 (2002)

[Publications] Wang J: "MyD88 is involved in signaling pathway for Taxol-induced apoptosis and TNF-α expression in human myelomonocytic cells"Br J. Haematol.. 118. 638-645 (2002)

[Publications] Zhao W: "Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II"Cancer Immunol. Immunother.. 51. 381-388 (2002)

[Publications] Masauji N: "Mean fluorescence intensity (MFI) of CD11b on CD34-positive (CD34+) cells derived from granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood (PB) correlate conversely with the total amount of harvested CD34+ cells"Ann Heamatol.. 81. 183-184 (2002)

[Publications] Suzuki S: "Autocrine production of epithelial cell-derived neutrophil attractant-78 (ENA-78) induced by G-CSF in neutrophils"Blood. 99. 1863-1865 (2002)

[Publications] Niizeki H: "Hypoxia enhances the expression of autocrine motility factor and the motility of human pancreatic cancer cells"Br J Cancer. 86. 1914-1919 (2002)

[Publications] 小林正伸: "HIF-1(解説)"生化学. 74. 492 (2002)

[Publications] Wang J: "MyD88 is involved in signaling pathway for Taxol-induced apoptosis and TNF-α expression in human myelomonocytic cells"Br J. Haematol. 118. 638-645 (2002)

[Publications] Zhao W: "Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II"Cancer Immunol. Immunother.. 51. 381-388 (2002)

[Publications] Masauji N: "Mean fluorescence intensity (MFI) of CD11b on CD34-positive (CD34+) cells derived from granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood (PB) correlate conversely with the total amount of harvested CD34+ cells"Ann Heamatol.. 81. 483-484 (2002)

小林正伸北海道大学, 遺伝子病制御研究所, 助教授 (80241321)