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膵癌間質における酸化ストレス応答機構の解析

田中 裕 東北大学

2022.03.25

概要

膵癌は発見時既に進行例であることが多く、抗癌剤に対しても抵抗性である。組織学的には豊富な線維性間質が特徴であり、間質細胞である膵星細胞 (PSC) は膵線維化形成に中心的な役割を果たし、癌間質相互作用により癌の進展に寄与している。酸化ストレス応答機構の中核を担う Kelch-like ECH-associated protein 1 (KEAP1) -NF-E2-related 2 (NRF2) 経路は、様々な癌において発癌や抗癌剤耐性への関与が示されている。当教室の先行研究では、膵特異的に変異 K-ras,p53 を発現させた膵癌モデルマウス (KPC マウス)において、全身性の Nrf2 欠損により膵癌の進行が抑制されることが明らかになっているが、癌と間質どちらの Nrf2 が癌の進展に寄与しているか未解明であった。

PSC における Keap1-Nrf2 経路の役割を解明することを目的とし、以下の項目について検討した。The Cancer Genome Atlas データベース解析によりヒト膵癌における NRF2 標的遺伝子の発現を検討した。ヒト膵癌組織の免疫染色により膵癌間質における NRF2 標的分子の発現を確認した。野生型および Nrf2 欠損マウスの膵臓から分離した PSC を用いて、PSCにおける Nrf2 の役割や KPC マウス由来膵癌細胞株への作用を検討した。不死化 PSC 株と膵癌細胞株を用いた皮下移植モデルにて腫瘍形成能を比較した。

データベース解析によってヒト膵癌では NRF2 標的遺伝子の発現亢進を約 15%の頻度で認め、ヒト膵癌組織では活性化したPSC の一部にNRF2 標的分子の発現を認めた。野生型 PSC (WT-PSC) と比べ、Nrf2 欠損 PSC (Nrf2-/--PSC) は酸化ストレス耐性だけでなく増殖能や遊走能も低下していた。また Nrf2-/--PSC の conditioned medium は、膵癌細胞の増殖を促進させる作用が低下していた。皮下移植モデルにおいて、WT-PSC 株と膵癌細胞株の共移植によって腫瘍は増大したが、Nrf2-/--PSC 株との共移植では腫瘍増大効果が減弱した。さらに Nrf2 の欠損した膵癌細胞株でも検証したところ、同様の結果が得られた。癌細胞側の Nrf2 の有無によらず、PSC における Nrf2 は癌を促進させることが示された。

本研究により、PSC の Nrf2 は酸化ストレス応答だけでなく細胞増殖や遊走、活性化に関与しており、癌促進的な作用を持つことが示された。膵癌細胞の増殖を促進させるメディエーターの同定には至らなかったが、可溶性因子を介した作用であることが示唆された。膵癌間質の Nrf2 を標的とした治療応用に向けて、さらなる知見の集積が期待される。

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