1994 Fiscal Year Annual Research Report

HGFからみた癌細胞と間質細胞の相互作用に関する分子細胞生物学的解析

Research Project

Project/Area Number	06780585
Research Institution	Osaka University
Principal Investigator	松本邦夫大阪大学, 医学部, 講師 (90201780)
Keywords	HGF / c-met / 癌転移 / 癌-宿主相互作用
Research Abstract	がん細胞の増殖能や侵潤・転移能はがん細胞をとりまく宿主細胞との相互作用を介して大きく影響されることががん細胞-宿主相互作用として知られてきた。本年度は宿主間質に由来するHGFならびにがん細胞に由来するHGF誘導因子ががん細胞-宿主相互作用のメデイエーターとして、がん細胞の悪性化に関与することを明らかにした。胆のうがんは一般に高転移性で致死率の高い悪性のがんである。ヒト胆のうがん細胞は宿主組織内では高い侵潤能を有するものの、コラーゲンゲル上に培養しても自らゲル内に侵潤することはない。ところが、正常線維芽細胞とコラーゲンゲルをはさんでco-cultureすると胆のうがん細胞はゲル内に侵潤し、液性因子を介した間質細胞との相互作用が胆のうがん細胞の侵潤能を誘導している。しかも、このco-culture系でのがん細胞の侵潤はHGFに対する抗体により完全にブロックされ、間質由来の侵潤因子の実態はHGFであることを明らかにした。さらに胆のうがん細胞のゲル内侵潤はHGF以外での代表的な増殖因子では誘導されず、HGFは強力な侵潤誘導因子であるといえる。一方、興味深いことにがん細胞は間質線維芽細胞に対しHGFの産生を高める因子を産生、このHGF誘導因子(インジュリン)の実体はIL-1βであることを明らかにした。また同様に線維芽細胞が産生する口腔粘膜上皮がん細胞に対する侵潤誘導因子の実体もHGFであることを明らかにした。その他、ヒト肺小細胞がんやオリゴデンドログリオーマの中にはvariant HGFを産生し、しかもこれらの細胞においては、HGFがオートクリン的にがん細胞の運動性や侵潤能を高めていることを明らかにした。一方、HGFによるmotilityの亢進にはp125^<FAK>(focal adhesion kinase)を一過的なリン酸化が関与することを明らかにした。p125^<FAK>はβ1インテグリン結合することが知られており、HGF刺激後、初期のfocal adhesionの形成、細胞骨格の再構成にはp125^<FAK>のリン酸化が関与しており、HGFによる細胞のmotility亢進において細胞-マトリックスとの相互作用はp125^<FAK>を介して調節されていると思われる。これらの観点から、HGFによる侵潤をブロックするアンタゴニストの開発は今後がん治療という点で極めて重要になることが予測される。

Research Products
(20 results)

All Other

All Publications (20 results)

[Publications] H.Okazaki: "Prital purification and characterizaiton of "Injurin-like factor" which stimulates production of hepatocyte growth factor." Biochem.Biophys.Acta. 1220. 291-298 (1994)
[Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. 91. 4357-4361 (1994)
[Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. 10. 145-151 (1994)
[Publications] O.F.P.Santos: "Involvement of Hepatocyte growth factor in kidney development." Develop.Biol.163. 525-529 (1994)
[Publications] Y.Itakura: "Autocrine stimulation of motility in SBC-5 human lung carcinoma cells by a two-kringle variant of HGF." Cancer Lett.71. 35-41 (1994)
[Publications] K.Matsumoto: "Hepatocyte growth factor/scatter foctor induces tyrosine phosphonlation of facal adhesion kinsase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells." J.Biol.Chem.269. 31807-31813 (1994)
[Publications] T.Kobayashi: "Hepatocyte growth factor elevates the activity levels of glycolopid sulfotransferase in renal cell carcinoma cells." Eur.J.Biochem.219. 407-413 (1994)
[Publications] T.Kobayashi: "Hepatocyte growth factor specifically binds to sulfoglycolipids." J.Biol.Chem.269. 9817-9821 (1994)
[Publications] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasis by the paracrine system." J.Biochem.117. 671-676 (1995)
[Publications] N.Nakayama: "Differing distribution of hepatocyte growth factor-positive cells in the liver of LEC rats with acute hepatitis,chronic hepatitis and hepatoma." Jap.J.Concer Res.86. 5-9 (1995)
[Publications] K.Matsumoto: "Novel function of prostaglandins as inducer of gene expression of fepatocyte growth factor and putative mediator of tissue regeneration." J.Biochem.117. 458-464 (1995)
[Publications] A.Yamada: "Rapid and sensitive enzyme-linked immunosorbent assay for measurement of HGF in rat and human tissues." Biomed.Res.(in press). (1995)
[Publications] T.Sato: "Hepatocyte growth factor (HGF) is in volved in the formation of osteoclast-like cells mediated by clonal stromal cells (MC3T3-G1/PA6)." J.Cell.Physiol.(in press). (1995)
[Publications] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic,motogenic and morphogenetic activities on chondrocytes." J.Cell Biol.(in press). (1995)
[Publications] K.Matsumoto: "Pleiotropic roles of HGF in mitogenesis,morphogenesis and organ regeneration." Gann Monograph No.42 : Growth Factors : Cell Growth,Morphogenesis and Transformation, 21 (1994)
[Publications] K.Matsumoto: "Hepatotrophic and renotrophic activities of HGF in vivo : Possible application of HGF for hepatic and renal diseases." Springer Verlag, 14 (1994)
[Publications] K.Matsumoto: "Structure,pleiotropic actions,and organotrophic roles of hepatocyte growth factor." Springer Verlag, 21 (1994)
[Publications] K.Matsumoto: "Pleiotropic roles of HGF as a mediator of epithelial-mesenchymal interactions." Organizing Committee for the Eighth International Conference of the International Society of Differentiation., 4 (1994)
[Publications] K.Matsumoto: "Primary and continuous cell culture : Collagenase and Hyaluronidase." John Wiley & Sons Limited, in press (1995)
[Publications] K.Matsumoto: "Hepatocyte growth factor as a renotropic factor and therapeutic potential for acute renal failure." Churchill Livingstone, in press (1995)

1994 Fiscal Year Annual Research Report

HGFからみた癌細胞と間質細胞の相互作用に関する分子細胞生物学的解析

Principal Investigator

松本 邦夫 大阪大学, 医学部, 講師 (90201780)

Research Products

[Publications] H.Okazaki: "Prital purification and characterizaiton of "Injurin-like factor" which stimulates production of hepatocyte growth factor." Biochem.Biophys.Acta. 1220. 291-298 (1994)

[Publications] K.Kawaida: "Hepatocyte growth factor prevent acute renal failure and accelerate renal regeneration." Proc.Nalt.Acad.Sci.USA. 91. 4357-4361 (1994)

[Publications] O.Amano: "Expression and localization of hepatocyte growth factor in rat submandibular gland." Growth Factors. 10. 145-151 (1994)

[Publications] O.F.P.Santos: "Involvement of Hepatocyte growth factor in kidney development." Develop.Biol.163. 525-529 (1994)

[Publications] Y.Itakura: "Autocrine stimulation of motility in SBC-5 human lung carcinoma cells by a two-kringle variant of HGF." Cancer Lett.71. 35-41 (1994)

[Publications] K.Matsumoto: "Hepatocyte growth factor/scatter foctor induces tyrosine phosphonlation of facal adhesion kinsase (p125FAK) and promotes migration and invasion by oral squamous cell carcinoma cells." J.Biol.Chem.269. 31807-31813 (1994)

[Publications] T.Kobayashi: "Hepatocyte growth factor elevates the activity levels of glycolopid sulfotransferase in renal cell carcinoma cells." Eur.J.Biochem.219. 407-413 (1994)

[Publications] T.Kobayashi: "Hepatocyte growth factor specifically binds to sulfoglycolipids." J.Biol.Chem.269. 9817-9821 (1994)

[Publications] S.Saito: "Hepatocyte growth factor promotes the growth of cytotrophoblasis by the paracrine system." J.Biochem.117. 671-676 (1995)

[Publications] N.Nakayama: "Differing distribution of hepatocyte growth factor-positive cells in the liver of LEC rats with acute hepatitis,chronic hepatitis and hepatoma." Jap.J.Concer Res.86. 5-9 (1995)

[Publications] K.Matsumoto: "Novel function of prostaglandins as inducer of gene expression of fepatocyte growth factor and putative mediator of tissue regeneration." J.Biochem.117. 458-464 (1995)

[Publications] A.Yamada: "Rapid and sensitive enzyme-linked immunosorbent assay for measurement of HGF in rat and human tissues." Biomed.Res.(in press). (1995)

[Publications] T.Sato: "Hepatocyte growth factor (HGF) is in volved in the formation of osteoclast-like cells mediated by clonal stromal cells (MC3T3-G1/PA6)." J.Cell.Physiol.(in press). (1995)

[Publications] T.Takabayashi: "Hepatocyte growth factor/scatter factor has mitogenic,motogenic and morphogenetic activities on chondrocytes." J.Cell Biol.(in press). (1995)

[Publications] K.Matsumoto: "Pleiotropic roles of HGF in mitogenesis,morphogenesis and organ regeneration." Gann Monograph No.42 : Growth Factors : Cell Growth,Morphogenesis and Transformation, 21 (1994)

[Publications] K.Matsumoto: "Hepatotrophic and renotrophic activities of HGF in vivo : Possible application of HGF for hepatic and renal diseases." Springer Verlag, 14 (1994)

[Publications] K.Matsumoto: "Structure,pleiotropic actions,and organotrophic roles of hepatocyte growth factor." Springer Verlag, 21 (1994)

[Publications] K.Matsumoto: "Pleiotropic roles of HGF as a mediator of epithelial-mesenchymal interactions." Organizing Committee for the Eighth International Conference of the International Society of Differentiation., 4 (1994)

[Publications] K.Matsumoto: "Primary and continuous cell culture : Collagenase and Hyaluronidase." John Wiley & Sons Limited, in press (1995)

[Publications] K.Matsumoto: "Hepatocyte growth factor as a renotropic factor and therapeutic potential for acute renal failure." Churchill Livingstone, in press (1995)

松本邦夫大阪大学, 医学部, 講師 (90201780)