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変動する機械的圧縮刺激に対するメラノーマ細胞の応答性に関する研究 (本文)

森倉, 峻 慶應義塾大学

2022.03.23

概要

近年,メラノーマの発症率が世界的に増加し続けていることが報告されており,メラノーマに対する効果的な治療法の確立が切望されている[1]–[3].進展が極めて早いメラノーマは他の悪性腫瘍に比べて高い死亡率を示し,予後の悪い難治性疾患である[4].ダカルバジン抗がん剤を用いた化学療法[5],[6]が長年支持されてきたが,アナフィラキシーショックや重篤な肝障害などの極めて深刻な副作用[7],[8]を示す一方で奏効率は低いことが重大な懸念事項であった[9].そこで,近年の分子生物学の隆盛を受けて,特定の遺伝子変異を治療ターゲットとする分子標的療法[10],[11]や,免疫阻害チェックポイント剤を用いた免疫療法[12],[13]などの画期的な治療法が次々と開発された.これらの治療法はメラノーマのメジャーサブタイプである,表在性拡がり型メラノーマ(superficial spreading melanoma: SSM)に対して効果を発揮した.SSMは顔や腕などの紫外線曝露部に発症するため,紫外線曝露を起因とした多くの遺伝子変異が認められている[14]–[19].特定の遺伝子変異をターゲットとした分子標的療法や免疫療法は,SSMに対し極めて高い奏効率を示すことが知られている[20]–[23].しかしながら,主に足裏に発症するマイナーサブタイプの末端黒子型メラノーマ(acral lentiginous melanoma: ALM)は,紫外線曝露との関連性が低く遺伝子変異の発生自体が少ないため[24],[25],分子標的療法や免疫療法などの新たな治療法に対する感受性が未だ低い[26].したがって,ALMのような紫外線曝露との関連性の低いマイナーサブタイプに対しても効果的な治療法を開発することが強く求められている.ここで,マイナーサブタイプの進展プロセスには,紫外線曝露による遺伝子変異とは全く異なるプロセスが存在すると指摘されている[27],[28].近年,メラノーマの進展プロセスに与える新たな因子として,メラノーマを囲む物理環境や機械的刺激が注目され始めた.Minagawaらは,臨床試験において機械的刺激が強く負荷される部位においてメラノーマの進展が促進されていることを報告した[29].Liuらは静的な物理的環境の違いによってメラノーマの進展が変化することを報告した[30].以上のように,メラノーマは静的な機械的刺激に応答して進展プロセスを変化させることが徐々に明らかとなってきた.しかしながら,生体内で発生する機械的刺激や物理環境は常に変動するため,メラノーマの進展プロセスを深く理解するためには変動する機械的刺激下における応答性を解明する必要があるが,現時点でほとんどのプロセスが未解明である.

そこで,本研究では,変動する機械的圧縮刺激に対するメラノーマ細胞の応答性を細胞集団レベルおよび単一細胞レベルで解明する(図1.1).次節以降,本研究の目的を達成するために必要な以下2つの要素を説明する.
1.機械的圧縮刺激印加培養装置(1.2節)
2.四次元細胞顕微鏡法(1.3節)

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