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损失p53触发了依赖WNT的全身炎症,导致乳腺癌转移
Max D Wellenstein1, Seth B Coffelt1,2,3, Danique E M Duits1
1Division of Tumour Biology & Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nature
|August 2, 2019
概括
乳腺癌细胞中的p53损失通过促进中性粒细胞活动驱动炎症和转移. 阻断这些细胞中的WNT分泌会减少炎症和转移,从而提供新的治疗点.
科学领域:
- 癌症学
- 免疫学
- 分子生物学
背景情况:
- 系统性炎症,以高的中性粒细胞与淋巴细胞的比率来表示,与癌症的不良结果相关.
- 中性粒细胞在癌症转移中起着因果作用.
- 癌症中的全身性中性友炎异质性背后的机制尚不清楚.
研究的目的:
- 研究癌细胞内在的p53在调节乳腺癌系统性中性恋炎症和转移中的作用.
- 阐明将p53状态与转移性炎症联系在一起的分子机制.
主要方法:
- 使用16个基因工程小鼠模型的乳腺癌.
- 分析了p53损失对WNT连体分泌,巨细胞激活 (IL-1β产生) 和全身性中性恋的影响.
- 使用药理和遗传策略阻断p53-null癌细胞中的WNT分泌.
主要成果:
- 癌细胞中的p53损失诱导了WNT连接体的分泌,刺激与瘤相关的巨细胞产生IL-1β.
- 这导致了全身炎症和转移.
- 在p53- null细胞中阻断WNT分泌逆转了IL-1β的产生和中性友炎症,减少了转移.
结论:
- 癌细胞内在的p53是前转移性中性粒细胞的关键调节剂.
- 在p53损失,WNT分泌和全身性中性恋之间存在机制性联系,这会增强转移性进展.
- 瘤的遗传构成会影响转移性炎症, 这表明个性化免疫干预策略.
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