2001 年度実績報告書

上皮・間葉相互作用によるがん悪性化の分子機構とその制御

研究課題

研究課題/領域番号	12215082
研究機関	大阪大学
研究代表者	中村敏一大阪大学, 医学系研究科, 教授 (00049397)
研究分担者	船越洋大阪大学, 医学系研究科, 助手 (40273685) 松本邦夫大阪大学, 医学系研究科, 助教授 (90201780)
キーワード	上皮・間葉相互作用 / HGF / がん悪性化 / NK4 / 制癌 / 浸潤 / 転移 / 腫瘍血管新生
研究概要	1)HGFは間質由来因子として癌の浸潤・転移を駆動することから、私達は癌悪性化を阻止すべくHGFアンタゴニスト(NK4/malignostatin)を調整して来た。今回、ヒト膵癌同所移植モデルを用いてNK4の強力なin vivo制癌効果はHGFアンタゴニストと血管新生阻害活性の2つの機能を持つことにより達成されることを実証した。即ち、NK4は癌の初期ではHGFアンタゴニストとして浸潤を阻止する一方、進行期では血管新生阻害因子として浸潤癌の成長・転移形成をブロックすると考えられた。一方、NK4による血管内皮細胞のDNA合成阻害にはサイクリンD1の発現抑制およびRbのリン酸化阻止が重要であることを初めて明らかにした。このことから、NK4は血管内皮での細胞周期、即ち、G1期からS期への進展を阻害することでgrowth arrestの状態を維持し、腫瘍血管新生を抑制すると考えられた。私達は既にNK4遺伝子治療によっても強力な制癌効果が得られることを明らかにしており、NK4またはその遺伝子は膵癌を始めとする様々な腫瘍疾患に対して有効な制癌剤となることが期待される。 2)傷害認知によって誘導されるHGFは肺再生、肝再生を駆動する必須の生理的因子であることが今回のHGF中和抗体を用いた研究から実証された。HGFおよびその受容体であるc-Metは多くの臓器において生体修復システムを構成し、傷害臓器での組織修復・生理的機能の回復に寄与していると考えられる。一方、このような生理活性を有するHGFの利用は腎移植を始めとする多くの移植医療で安全な移植技術の確立に向けて大きな意味を持つ。一方、神経変性疾患は高齢化社会が抱える最重要課題の1つであるが、ALSやアルツハイマー病などの様々な難治性神経疾患の治療法確立に向けてHGFによるニューロン細胞死阻止は重要な治療戦略と成りうると考えられる。

研究成果

(51件)

すべてその他

すべて文献書誌 (51件)

[文献書誌] T.Sumi, et al.: "Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho-and Cdc42-activated LIM-kinase2"J.Cell Biol.. 147. 1519-1532 (1999)
[文献書誌] T.Ueki, et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats"Nature Medicine. 5. 226-230 (1999)
[文献書誌] M.Tahara, et al.: "Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats"J.Clin.Invest. 103. 313-320 (1999)
[文献書誌] R.Hasina, et al.: "Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line"Brit.J.Cancer. 80. 1708-1717 (1999)
[文献書誌] N.Taniura-Matsumoto, et al.: "Prostaglandin production in mouse mammary carcinoma cells confers invasive growth potential by inducing hepatocyte growth factor in fibroblasts"Brit.J.Cancer. 81. 194-202 (1999)
[文献書誌] K.Kosai, et al.: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)
[文献書誌] Y.Kawano, et al.: "Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo"J.Cell Biol.. 147. 1023-1037 (1999)
[文献書誌] A.Uchiyama, et al.: "Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural fluid by surgery in lung cancer patients"Brit.J.Cancer. 81. 721-726 (1999)
[文献書誌] W.G.Jiang, et al.: "Antagonistic effect of NK4, a novel HGF variant, on in vitro angiogenesis of human vascular endothelial cells"Clin.Cancer Res.. 5. 3695-3703 (1999)
[文献書誌] C.Parr, et al.: "NK4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the matility and invasion of colon cancer cells"Intern.J.Cancer. 85. 563-570 (1999)
[文献書誌] K.Kuba, et al.: "HGF/NK4, a four-kringle fragment of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice"Cancer Res.. 60. 6737-6743 (2000)
[文献書誌] T.Nakamura, et al.: "Myocardial protection from infarction by endogenous and exogenous hepatocyte growth factor"J.Clin.Invest.. 106. 1511-1519 (2000)
[文献書誌] S.Mizuno, et al.: "Reciprocal balance of hepatocyte growth factor and transforming growth factor-beta1 In renal fibrosis in mice"Kidney Intern.. 57. 937-948 (2000)
[文献書誌] T.Yamada, et al.: "Enhanced expression of hepatocyte growth factor by pulmonary ischemia reperfusion injury in the rat"Am.J.Resp. Crit Care Med.. 162. 707-715 (2000)
[文献書誌] S.Hiscox, et al.: "Inhibition of HGF-induced breast cancer cell matility and invasion by the HGF variant NK4"Breast Cancer Res. & Treat.. 59. 245-254 (2000)
[文献書誌] K.Beppu, et al.: "Elevation of serum hepatocyte growth factor concentration in patients with gastric cancer is mediated by production by tumor tissue"Anticancer Res.. 20. 1263-1268 (2000)
[文献書誌] T.Sumi, et al.: "Specific activation of LIM-kinase 2 via threonine-505 phosphoiylation by ROCK under the control of Rho"J.Biol.Chem.. 276. 670-676 (2001)
[文献書誌] T.Sumi, et al.: "Activation of LIM-kinases by Myotonic dystrophy kinase-related Cdc 42-binding kinase-alpha"J.Biol.Chem.. 276. 23092-23096 (2001)
[文献書誌] S.Mizuno, et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intern.. 59. 1304-1314 (2001)
[文献書誌] K.Matsumoto, T.Nakamura: "Hepatocyte growth factor renotropic role and potential therapeutics for renal diseases"Kidney Intern.. 59. 2023-2038 (2001)
[文献書誌] K.Matsumoto, et al.: "Hepatocyte growth factor in renal regeneration, renal disease, and potential therapeutics"Current Opinion in Nephrogy and Hypertension. 8. 395-402 (2001)
[文献書誌] T.Kuroiwa, et al.: "Hepatocyte growth factor ameliorates acute graft-verus-host disease and promotes hematopoietic function"J.Clin.Invest.. 107. 1365-1373 (2001)
[文献書誌] N.Maehara, et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)
[文献書誌] H.Azuma, et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol.. 12. 1280-1292 (2001)
[文献書誌] T.Nakamura: "Molecular cloning and characterization of Kremen, a novel Kringle-containing transmembrane protein"Biochem.Biophys.Acta. 93513. 1-10 (2001)
[文献書誌] D.Tomioka, et al.: "Inhibition of growth, invasion and metastasis of human panereatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)
[文献書誌] Y.Taniyama, et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hind limb ischemia models : Preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)
[文献書誌] K.Hayashi, et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor in vivo gene transfer of HGF to subarachiroid space prevents delayed neuronal death in gerbil hipopocampal CA1 neurons"Gene Therapy. 8. 1263-1268 (2001)
[文献書誌] H.Takahashi, et al.: "Impaired spematogenic ability of testicular germ cells in mice dificient in the LIM-kinase 2 gene"Develop.Biol.. 241. 259-272 (2002)
[文献書誌] T.Sumi, et al.: "Mitosis-Dependent Phosphorylation and Activation of LIM-Kinase 1"Biochem.Biophys.Res.Commun.. 290. 1315-1320 (2002)
[文献書誌] H.Funakoshi, et al.: "Identification of Gas 6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neursci.Res.. (In press). (2002)
[文献書誌] Y.Taniyama, et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : Molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2002)
[文献書誌] H.Shibuki, et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemic-reperfusion injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)
[文献書誌] Y.Sakamaki, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (In press). (2002)
[文献書誌] 松本邦夫: "HGFによる再生医学の実践-肝臓と腎臓を中心として"実験医学. 18. 424-430 (1999)
[文献書誌] 松本邦夫, 他: "HGFの分子内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)
[文献書誌] 松本邦夫, 他: "二面性癌悪化性阻止分子HGF/NK4による新しい癌治療"治療. 82. 1642-1644 (2000)
[文献書誌] 船越洋, 他: "HGFの神経系における機能と神経疾患治療への展望"神経研究の進歩. 44. 414-422 (2000)
[文献書誌] 松本邦夫, 他: "浸潤・転移ならびに血管新生阻害作用を有するHGFの分子内断片NK4による癌悪性化阻止"生物物理化学. 44. 119-124 (2000)
[文献書誌] 小清水右一, 他: "HGFと形態形成"現代治療. 32. 1931-1938 (2000)
[文献書誌] 久場啓司, 他: "NK4による癌の浸潤・転移抑制と腫瘍血管新生阻害"分子がん治療. 1. 46-55 (2000)
[文献書誌] 前原直樹, 他: "新規浸潤・転移/血管新生阻止因子NK4(malignostatin)による癌治療"Cancer Frontier. 2. 61-68 (2000)
[文献書誌] 仲村輝也, 他: "HGF(肝細胞増殖因子)-臓器再生・保護機能と再生治療への応用-"救急医学. 24. 1604-1610 (2000)
[文献書誌] 松本邦夫, 他: "NK4(malignostatin)による癌悪性化防止:浸潤・転移・血管新生阻止による新しい制癌戦略"最新医学. 55. 1960-1968 (2000)
[文献書誌] 富岡大策, 他: "HGFを介した腫瘍血管新生とNK4による制癌"医学のあゆみ. 194. 792-798 (2000)
[文献書誌] 松本邦夫, 他: ""肝細胞の培養法"「細胞生物学実験法I」"広川書店. 20 (1999)
[文献書誌] K.Matsumoto, et al.: "Hepatocyte growth factor and Met in tumour invasion-metastasis : from mechanisms to cancer prevention. In "Cancer Metastasis : Molecular & Cellular Mechanisms and Clinical Interventions""Kluwer Academic Publishers. 50 (2000)
[文献書誌] K.Matsumoto, et al.: "HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4. In "Growth Factors and Their Receptors in Cancer Metastasis""Kluwer Academic Publishers. 35 (2001)
[文献書誌] K.Matsumoto, et al.: "分担: HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名: Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher. 35 (2001)
[文献書誌] 水野信哉, 中村敏一: "先端医療シリーズ7・泌尿器科:診断と治療の最前線"先端医療技術研究所. 11 (2000)
[文献書誌] 水野信哉, 中村敏一: "Annual Review 腎臓2000"中外医学社. 8 (2000)

2001 年度 実績報告書

上皮・間葉相互作用によるがん悪性化の分子機構とその制御

研究代表者

中村 敏一 大阪大学, 医学系研究科, 教授 (00049397)

研究成果

[文献書誌] T.Sumi, et al.: "Cofilin phosphorylation and actin cytoskeletal dynamics regulated by Rho-and Cdc42-activated LIM-kinase2"J.Cell Biol.. 147. 1519-1532 (1999)

[文献書誌] T.Ueki, et al.: "Hepatocyte growth factor gene therapy of liver cirrhosis in rats"Nature Medicine. 5. 226-230 (1999)

[文献書誌] M.Tahara, et al.: "Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats"J.Clin.Invest. 103. 313-320 (1999)

[文献書誌] R.Hasina, et al.: "Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line"Brit.J.Cancer. 80. 1708-1717 (1999)

[文献書誌] N.Taniura-Matsumoto, et al.: "Prostaglandin production in mouse mammary carcinoma cells confers invasive growth potential by inducing hepatocyte growth factor in fibroblasts"Brit.J.Cancer. 81. 194-202 (1999)

[文献書誌] K.Kosai, et al.: "Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice"Hepatology. 30. 151-159 (1999)

[文献書誌] Y.Kawano, et al.: "Phosphorylation of myosin-binding subunit (MBS) of myosin phosphatase by Rho-kinase in vivo"J.Cell Biol.. 147. 1023-1037 (1999)

[文献書誌] A.Uchiyama, et al.: "Hepatocyte growth factor and invasion-stimulatory activity are induced in pleural fluid by surgery in lung cancer patients"Brit.J.Cancer. 81. 721-726 (1999)

[文献書誌] W.G.Jiang, et al.: "Antagonistic effect of NK4, a novel HGF variant, on in vitro angiogenesis of human vascular endothelial cells"Clin.Cancer Res.. 5. 3695-3703 (1999)

[文献書誌] C.Parr, et al.: "NK4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the matility and invasion of colon cancer cells"Intern.J.Cancer. 85. 563-570 (1999)

[文献書誌] K.Kuba, et al.: "HGF/NK4, a four-kringle fragment of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice"Cancer Res.. 60. 6737-6743 (2000)

[文献書誌] T.Nakamura, et al.: "Myocardial protection from infarction by endogenous and exogenous hepatocyte growth factor"J.Clin.Invest.. 106. 1511-1519 (2000)

[文献書誌] S.Mizuno, et al.: "Reciprocal balance of hepatocyte growth factor and transforming growth factor-beta1 In renal fibrosis in mice"Kidney Intern.. 57. 937-948 (2000)

[文献書誌] T.Yamada, et al.: "Enhanced expression of hepatocyte growth factor by pulmonary ischemia reperfusion injury in the rat"Am.J.Resp. Crit Care Med.. 162. 707-715 (2000)

[文献書誌] S.Hiscox, et al.: "Inhibition of HGF-induced breast cancer cell matility and invasion by the HGF variant NK4"Breast Cancer Res. & Treat.. 59. 245-254 (2000)

[文献書誌] K.Beppu, et al.: "Elevation of serum hepatocyte growth factor concentration in patients with gastric cancer is mediated by production by tumor tissue"Anticancer Res.. 20. 1263-1268 (2000)

[文献書誌] T.Sumi, et al.: "Specific activation of LIM-kinase 2 via threonine-505 phosphoiylation by ROCK under the control of Rho"J.Biol.Chem.. 276. 670-676 (2001)

[文献書誌] T.Sumi, et al.: "Activation of LIM-kinases by Myotonic dystrophy kinase-related Cdc 42-binding kinase-alpha"J.Biol.Chem.. 276. 23092-23096 (2001)

[文献書誌] S.Mizuno, et al.: "Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy"Kidney Intern.. 59. 1304-1314 (2001)

[文献書誌] K.Matsumoto, T.Nakamura: "Hepatocyte growth factor renotropic role and potential therapeutics for renal diseases"Kidney Intern.. 59. 2023-2038 (2001)

[文献書誌] K.Matsumoto, et al.: "Hepatocyte growth factor in renal regeneration, renal disease, and potential therapeutics"Current Opinion in Nephrogy and Hypertension. 8. 395-402 (2001)

[文献書誌] T.Kuroiwa, et al.: "Hepatocyte growth factor ameliorates acute graft-verus-host disease and promotes hematopoietic function"J.Clin.Invest.. 107. 1365-1373 (2001)

[文献書誌] N.Maehara, et al.: "NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells"Br.J.Cancer. 84. 864-873 (2001)

[文献書誌] H.Azuma, et al.: "Hepatocyte growth factor prevents development of chronic allograft nephropathy in an experimental rat transplant model"J.Am.Soc.Nephrol.. 12. 1280-1292 (2001)

[文献書誌] T.Nakamura: "Molecular cloning and characterization of Kremen, a novel Kringle-containing transmembrane protein"Biochem.Biophys.Acta. 93513. 1-10 (2001)

[文献書誌] D.Tomioka, et al.: "Inhibition of growth, invasion and metastasis of human panereatic carcinoma cells by NK4 in an orthotopic mouse model"Cancer Res.. 61. 7518-7524 (2001)

[文献書誌] Y.Taniyama, et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hind limb ischemia models : Preclinical study for treatment of peripheral arterial disease"Gene Therapy. 8. 181-189 (2001)

[文献書誌] K.Hayashi, et al.: "Gene therapy for preventing neuronal death using hepatocyte growth factor in vivo gene transfer of HGF to subarachiroid space prevents delayed neuronal death in gerbil hipopocampal CA1 neurons"Gene Therapy. 8. 1263-1268 (2001)

[文献書誌] H.Takahashi, et al.: "Impaired spematogenic ability of testicular germ cells in mice dificient in the LIM-kinase 2 gene"Develop.Biol.. 241. 259-272 (2002)

[文献書誌] T.Sumi, et al.: "Mitosis-Dependent Phosphorylation and Activation of LIM-Kinase 1"Biochem.Biophys.Res.Commun.. 290. 1315-1320 (2002)

[文献書誌] H.Funakoshi, et al.: "Identification of Gas 6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons"J.Neursci.Res.. (In press). (2002)

[文献書誌] Y.Taniyama, et al.: "Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat diabetic hind limb ischemia model : Molecular mechanisms of delayed angiogenesis in diabetes"Circulation. 104. 2344-2350 (2002)

[文献書誌] H.Shibuki, et al.: "Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemic-reperfusion injury"Invest.Ophthalmol.Vis.Sci.. 43. 528-536 (2002)

[文献書誌] Y.Sakamaki, et al.: "Hepatocyte growth factor stimulates proliferation of respiratory epithelial cells during postpneumonectomy compensatory lung growth in mice"Am.J.Respir.Cell Mol.Biol.. (In press). (2002)

[文献書誌] 松本邦夫: "HGFによる再生医学の実践-肝臓と腎臓を中心として"実験医学. 18. 424-430 (1999)

[文献書誌] 松本邦夫, 他: "HGFの分子内断片NK4による血管新生阻害と制癌"Molecular Medicine. 37. 276-282 (2000)

[文献書誌] 松本邦夫, 他: "二面性癌悪化性阻止分子HGF/NK4による新しい癌治療"治療. 82. 1642-1644 (2000)

[文献書誌] 船越洋, 他: "HGFの神経系における機能と神経疾患治療への展望"神経研究の進歩. 44. 414-422 (2000)

[文献書誌] 松本邦夫, 他: "浸潤・転移ならびに血管新生阻害作用を有するHGFの分子内断片NK4による癌悪性化阻止"生物物理化学. 44. 119-124 (2000)

[文献書誌] 小清水右一, 他: "HGFと形態形成"現代治療. 32. 1931-1938 (2000)

[文献書誌] 久場啓司, 他: "NK4による癌の浸潤・転移抑制と腫瘍血管新生阻害"分子がん治療. 1. 46-55 (2000)

[文献書誌] 前原直樹, 他: "新規浸潤・転移/血管新生阻止因子NK4(malignostatin)による癌治療"Cancer Frontier. 2. 61-68 (2000)

[文献書誌] 仲村輝也, 他: "HGF(肝細胞増殖因子)-臓器再生・保護機能と再生治療への応用-"救急医学. 24. 1604-1610 (2000)

[文献書誌] 松本邦夫, 他: "NK4(malignostatin)による癌悪性化防止:浸潤・転移・血管新生阻止による新しい制癌戦略"最新医学. 55. 1960-1968 (2000)

[文献書誌] 富岡大策, 他: "HGFを介した腫瘍血管新生とNK4による制癌"医学のあゆみ. 194. 792-798 (2000)

[文献書誌] 松本邦夫, 他: ""肝細胞の培養法"「細胞生物学実験法I」"広川書店. 20 (1999)

[文献書誌] K.Matsumoto, et al.: "Hepatocyte growth factor and Met in tumour invasion-metastasis : from mechanisms to cancer prevention. In "Cancer Metastasis : Molecular & Cellular Mechanisms and Clinical Interventions""Kluwer Academic Publishers. 50 (2000)

[文献書誌] K.Matsumoto, et al.: "HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4. In "Growth Factors and Their Receptors in Cancer Metastasis""Kluwer Academic Publishers. 35 (2001)

[文献書誌] K.Matsumoto, et al.: "分担: HGF-c-Met receptor pathway in tumor invasion-metastasis and potential cancer treatment with NK4 書名: Growth Factors and Their Receptors in Cancer Metastasis"Kluwer Academic Publisher. 35 (2001)

[文献書誌] 水野信哉, 中村敏一: "先端医療シリーズ7・泌尿器科:診断と治療の最前線"先端医療技術研究所. 11 (2000)

[文献書誌] 水野信哉, 中村敏一: "Annual Review 腎臓2000"中外医学社. 8 (2000)

2001 年度実績報告書

中村敏一大阪大学, 医学系研究科, 教授 (00049397)