遺伝子組換えHGFレセプターアンタゴニストによる癌細胞の浸潤・転移抑制剤の開発

1996 Fiscal Year Annual Research Report

• Project/Area Number: 07557199
• Section: 試験
• Research Institution: Osaka University
• Principal Investigator: 中村 敏一 大阪大学, 医学部, 教授 (00049397)
• Co-Investigator(Kenkyū-buntansha): 河田 純男 大阪大学, 医学部, 教授 (90183285) ; 門田 守人 大阪大学, 医学部, 教授 (00127309) ; 船越 洋 大阪大学, 医学部, 助手 (40273685) ; 松本 邦夫 大阪大学, 医学部, 助教授 (90201780)
• Keywords: HGF / HGFアンタゴニスト / HGF / NK4 / c-Met / 癌-間質相互作用 / 浸潤・転移抑制剤 / 基底膜浸潤 / コラーゲンゲル内浸潤

Research Abstract

癌細胞の浸潤・転移能といった悪性形質は癌細胞とそれをとり囲む宿主間質細胞との相互作用によって付与されることが知られている。HGFならびにc-Met/HGFレセプターを中心に癌-間質相互作用を解析した結果、HGFならびにHGF誘導因子を介した局所的な癌細胞と間質細胞の相互作用こそが、癌-間質相互作用による癌細胞悪性化の分子機構の一つであることを我々は明らかにしてきた。このような観点からHGFの作用をブロックするアンタゴニストを開発することは新しい浸潤・転移抑制剤への可能性を持ち有意義なことと言える。HGFは69kDのα鎖と34kDのβ鎖からなるヘテロダイマー構造を有しており、リコンビナントHGFをエラスターゼにより限定分解するとα鎖のC末端付近で分解されα鎖(HGF/NK4)ならびにβ鎖(HGF/β)を得ることができた。HGF/NK4は単独でc-Met/HGFレセプターに結合できるものの、HGF活性を示さず、HGF/NK4はHGFの生物活性を特異的に阻害するHGFアンタゴニストとして作用することを明らかにした。今回、我々はこのHGFアンタゴニスト(HGF/NK4)がHGFの癌-間質相互作用をブロックすることができるかをin vitroの癌細胞の培養系を用いて詳細に解析した。その結果、HGFアンタゴニストはin vitroにおいて肺癌、乳癌、胆のう癌など様々な培養癌細胞に対して、HGFによって誘導される基底膜浸潤やコラーゲンゲル内浸潤をほぼ完全にブロックしてまさにHGFアンタゴニストとして機能することを証明した。現在、in vivoにおいてHGFアンタゴニストが癌の浸潤・転移を抑制するかどうかをヌードマウスを用いた系によって検討している。

Research Products

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