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Design of an anti-cancer drug screening model combined with three-dimensional cell culture and drug release system

新居 輝樹 Teruki Nii 東京理科大学 DOI:info:doi/10.20604/00003609

2021.06.09

概要

　現在の抗がん剤スクリーニングでは、一般的に培養皿で2次元培養されたがん細胞を用いて行われる。しかし、この培養職境は体内のがん環境と大きく異なるため、ヒト治験での抗がん剤効果を適切に予想することが難しいことが多い。そのため、がん環境の模倣が期待できる3次元細胞培養(以下、細胞凝集体)は抗がん剤スクリーニングに有用と考えられる。しかしながら、細胞凝集体内部への酸素や栄養分の供給が悪く、細胞が死滅するという問題があった。1つの解決法として、われわれは、これまでにゼラチンハイドロゲル粒子を細胞凝集体内部に組み込んだ細胞凝集体の作製を報告している。この粒子は、細胞活性化薬物や成長因子を徐放することができる。本研究では、薬物含有粒子を含む細胞凝集体を作製し、がん環境を模倣することを試みた。
　本論文は、「第1章(序論)、第2章、第3章、第4章、第5章、および第6章(総括)』で構成されている。

第1章　序輪
　再生医療の基本概念は、体本来がもつ自然治癒力を介して、損傷した生体組織を再生修復させることである。再生医療には、実際に臨床で患者を治療する「再生治療」と次世代の治療を支える「再生研究』がある。再生研究には、細胞を用いた薬の活性および毒性を評価する創薬研究がある。試験管の中で、細胞活性の高い細胞を用いることによって薬物の活性をより効率よく評価することが可能となる。細胞の活性を高めるために、2つの技術の活用が有用であると考えられる。1つは3次元細胞培養である。正常細胞は固体状の基材に接着できなければ、自動的に死滅する。そのため、細胞接着しにくい基材上で培養すると、自然と細胞同士が接着し、細胞は3次元の凝集体を形成する。実際に、肝細胞の凝集体は単独の肝細胞に比べて、細胞の生物活性は髙い。また、胚性幹細胞も凝集体を形成することで分化を始めることが知られている。細胞の活性を高めるためのもう1つの技術として、生体材料の活用が考えられる。現在の細胞培養は、ポリスチレン容器にて行われている。これは人工的に構築された環境であり、細胞の体内環境とは大きく異なる。そのため、このような人工的な環境の下で体内の細胞状態を調べるには限界がある。体内の細胞调辺環境に近い性質をもつ生体材料を活用することによって細胞活性を髙めることが期 待できる。

第2章　振盪培養がゼラチンハイドロゲル粒子含有細胞凝集体の生物学的機能に与える影響
　本研究では、ゼラチンハイドロゲル粒子のftを変化させ、かつ凝集体内郎への酸素や栄餐の供給状態を改善するために振盪馆養法を適用した。これらの工夫による細胞凝集体の機能変化について調べた。ゼラチンハイドロゲル粒子と細胞との混合比、振盪培養の有無によらず、U底well中に細胞凝集体の形成が見られた。細胞に対するゼラチンハイドロゲル粒子の混合比率が高くなるとともに、細胞凝集体のサイズは大きくなった。また、ゼラチンハイドロゲル粒子を含有した細胞凝集体において、培養2週間まではサイズは変化しなかったが、3週間後ではそのサイズが小さくなった。これは、細胞凝集体内のゼラチンハイドロゲル粒子の分解が影饗していると考えられる。ゼラチンハイドロゲル粒子の混合比率が低い場合には、静置埼養と比較して、振盪培養された細胞凝集体の細胞当たりのATP量とミトコンドリア活性は有意に高くなった。これに対して、ゼラチンハイドロゲル粒子比率が高くなると振盪培養による影響は見られなかった。これらの結果は、低いゼラチンハイドロゲル粒子比率では、振盪による埼養液の動きが、凝集体内の細胞機能に影響することを示している。

第3章　p53阻害剤を含んだゼラチンハイドロゲル粒子含有がん関連線維芽細胞凝集体を組み込んだがん浸潤モデル
　がんの浸澗は、がん転移において重要なプロセスである。このプロセスの研究には、体内のがん環境に近い培養条件でのがん浸澗モデルの作製が必要不可欠になる。がん細胞の周辺に豊富に存在するがん関連線維芽細胞(CAF)とがん細胞との相互作用が、がん浸澗に大きく影饗すると言われている。そこで本研究では、p53阻害剤を含んだゼラチンハイドロゲル粒子を組み込んだ3次元CAF凝集体とがん細胞の共培養を行った。細胞非接着処理したU底ブレートにCAFおよびp 53阻害剤含有ゼラチンハイドロゲル粒子を播種することで、粒子とCAFからなる凝集体を作製した。高濃度の薬物含有粒子-CAF凝集体では、空の粒子-CAF凝集体、および低濃度の薬物含有粒子-CAF凝集体に比べてalpha-smooth muscle actin(a-SMA)値が有意に上昇し、凝集体内部での薬物徐放によるCAF機能が増強された。また、薬物含有培地で培養された空の粒T-CAF凝集体では、同濃度の薬物含有粒子-CAF凝集体に比べて、a-SMA値が有意に低下した。モデル基底膜上にがん細胞を、膜下に薬物含有粒子-CAF凝集体を播種したところ、2次元培養CAF、または空の粒子-CAF凝集体播種の場合と比較して、有意にがん細胞の浸潤率が上昇した。さらに、マトリックスメタロプロテアーゼ阻害剤の添加により、がん細胞浸潤の抑制が見られた。以上の結果は、薬物徐放化粒子とCAFの3次元凝集体の利用ががん細胞の浸潤評価に有効であることを示している。

第4章　TGF-β1放出システムを組み込んだがん関連線維芽細胞凝集体のがん浸潤モデル
　この研究の目的は、試験管内でがん細胞の浸潤率を調節できるがん浸潤モデルを創製することである。 —般的に、①がん環境で分泌されているtransforming growth factor-βl(TGF-βl)によるがん関連線維芽細胞(CAF)凝集体の活性増強、②活性化されたCAF凝集体とがん細胞による相互作用の増大、③相互作用によるマトリックスメタロプロテアーゼ(MMP)の過剰産生、そして④MMPによって分解された基底膜をがん細胞が通過することをがん浸潤とよぶ。一連のプロセスを試験管内で再現するために、まず「TGF-βI徐放粒子を含むCAF凝集体」を作製した。このTGF-βl徐放粒子を含むCAF凝集体のalpha-smooth muscle actin値は、2次元培養CAF、および空の粒子を含むCAF凝集体と比較して有意に上昇した。このことは、CAFの3次元組織化とDDS技術との組み合わせが、試験管内でもCAFの活性を高めたことを示している。次に、TGF-βl徐放粒子を含むCAF凝集体をモデル基底膜を介してがん細胞と共培養したところ、2次元培養CAF、および空の粒子を含むCAF凝集体播棰群と比較して、がん細胞の浸潤率が有意に上昇した。さらに、がん細胞の浸潤率とTGF-βlの濃度に正の相関性が得られた。このことは、TGF-βlの濃度を変化させることで試験管内でがん細胞の浸潤率をコントロールすることができることを示している。このモデルはがん細胞の浸潤率や治療効果を試験管内で評価するための有用なツールとなり得る。

第5章　がん細胞浸潤のための生傳分子放出を組み込んだ3 次元がん関連マクロファージと3次元がん関連線維芽細胞の共培養システム
　がん関連マクロファージ(TAM)は、がん細胞周辺に豊富に存在する間質細胞の一つであり、がん細胞の増殖、浸潤、転移、および薬剤抵抗性などに関与する重要な細胞である。
　このTAMを体内に近い状態で培養するためには、3次元培養とTAM機能を維持する薬物の持続的投与との組み合わせが有効である。そこで、本研究では、アデノシン含有ゼラチンハイドロゲル粒子を含むTAMの3次元凝集体を調製した。ヒト単球細胞株(THP-1)をホルボール12-ミリステート13-アセテートで刺激し、リポ多糖およびアデノシンを添加することで、TAMを得た。細胞非接着性処理をしたU底wellで、TAMとアデノシン徐放化粒子を共培養することで、アデノシン含有粒子を含むTAM凝集体を作製した。このTAM凝集体からの血管内皮増殖因子(VEGF)分泌量は、2次元培養TAMおよび空の粒子を含むTAM凝集体と比較して有意に上昇し、TAM機能の増強が確認された。次に、モデル基底膜上に肝がん細胞株(HepG2)を、膜下にアデノシン含有粒子を含むTAM凝集体を培養した。その結果、他のコントロールと比較して、有意にがん細胞の浸潤率は増大した。以上の結果は、アデノシン徐放化粒子を含むTAMの3次元凝集体の利用が、TAM機能の維持およびがん細胞の浸潤評価に有効であることを示している。さらに、transforming growth factor-β1含有粒子を含むCAF凝集体とアデノシン含有粒子を含むTAM凝集体の混合比率を変化させることで、肝がん細胞株に加えて、乳がん細胞株や肺がん細胞株でのがん細胞の浸澗を評価することが可能となった。

第6章総括
　3次元細胞培養とDrug Delivery System技術を融合させることにより、再生研究の重要な柱の一つである創薬研究への応用に期待できる。

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