Apc変異細胞は,腸内腫瘍の発症におけるスーパーコンペティターとして作用する

Sanne M van Neerven^1,2, Nina E de Groot^1,2, Lisanne E Nijman^1,2

¹Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Nature

|June 3, 2021

まとめ

変異性腸幹細胞 (ISC) は,WNT抗体を分泌することによって,健康な隣人を排除する. リチウム塩化物治療は,この拡大を阻害し,高リスクの個人に結腸癌の形成を防ぐ戦略を示唆しました.

科学分野:

細胞生物学
癌生物学
胃腸内科

背景:

腸の幹細胞 (ISC) のニッチは,腸内膜の更新のためにWNT信号のバランスを必要とします.
APC腫瘍抑制遺伝子の変異はこのバランスを崩し WNT経路の活性化と結腸癌を引き起こします
Apc変異細胞は,ワイルド型ISCよりも競争上の優位性を発揮し,しばしばクローンの拡大とがんの発症につながる.

研究の目的:

Apc-変異性ISCの競争上の優位性の背後にあるメカニズムを調査する.
Apc変異体が野生型の隣人を積極的に排除しているのかそれとも細胞内にあるのか
結腸がん予防におけるISC競争を標的とした治療戦略を探求する.

主な方法:

腸内ニッチでのAPC変異体と野生型のISCを研究した.
ISC競争におけるWNTアンタゴニストの役割を分析した.
リチウム塩化物治療を用いて,Apc変異性クローン拡大とアデノマ形成に対する効果を評価した.

主要な成果:

Apc変異のISCは,WNT抗体分泌によってスーパーコンペティターとして作用し,隣接するワイルド型ISCの差別化を誘導する.
リチウム塩化物治療は Apc- 変異性クローンの拡大とアデノマの形成を防ぎました.
この効果は,GSK3β抑制と下流のWNT活性化により,WNT抗体に対する野生型ISCの無感化によって媒介された.

結論:

Apc-変異したISCは,野生型の隣人を積極的に排除し,競争上の優位性に貢献します.
WNTシグナル伝達を調節することで健康な細胞のフィットネスを高めることは大腸がんの予防のための潜在的な戦略です
ISCコンペティションをターゲットにすることで大腸がんを発症するリスクの高い患者に新しい治療法を提供できるかもしれません

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