荷兰癌症研究所Karin E. de Visser和Jos Jonkers研究组发现了p53的缺失会引发wnt依赖的全身炎症，从而导致乳腺癌转移。该项研究成果发表在2019年8月22日出版的《自然》上。

据报道，该研究组使用一组16种不同的基因工程编辑的乳腺癌的小鼠模型，揭示癌细胞内在的p53作为转移性中性粒细胞的关键调节因子的作用。在机制上，癌细胞中p53的缺失诱导WNT配体的分泌，WNT配体能够刺激肿瘤相关巨噬细胞产生IL-1β，从而驱动系统性炎症。 p53缺失的癌细胞中WNT分泌的药理学和遗传学阻断逆转巨噬细胞产生IL-1β和随后的中性粒细胞炎症的发生，导致转移形成减少。总之，他们证明了癌细胞中p53的缺失，WNT配体的分泌和增强转移进展的系统性中性白细胞增多症之间的机制联系。这些发现阐明了乳腺肿瘤基因组成在决定转移性全身炎症中的重要性，并为制定癌症患者的个性化免疫干预策略奠定了基础。

据介绍，癌症相关的全身性炎症与癌症患者的疾病预后不良密切相关。对于大多数人类上皮肿瘤类型，高系统性中性粒细胞与淋巴细胞的比率与较差的总体存活率相关，实验结果表明中性粒细胞与转移之间存在因果关系。然而，决定肿瘤携带宿主之间系统性中性粒细胞炎症的实质异质性的癌细胞内在机制在很大程度上尚未得到解决。

附：英文原文

Title: Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis

Author: Max D. Wellenstein, Seth B. Coffelt, Danique E. M. Duits, Martine H. van Miltenburg, Maarten Slagter, Iris de Rink, Linda Henneman, Sjors M. Kas, Stefan Prekovic, Cheei-Sing Hau, Kim Vrijland, Anne Paulien Drenth, Renske de Korte-Grimmerink, Eva Schut, Ingrid van der Heijden, Wilbert Zwart, Lodewyk F. A. Wessels, Ton N. Schumacher, Jos Jonkers, Karin E. de Visser

Issue&Volume: Volume 572 Issue 7770

Abstract: Cancer-associated systemic inflammation is strongly linked to poor disease outcome in patients with cancer1,2. For most human epithelial tumour types, high systemic neutrophil-to-lymphocyte ratios are associated with poor overall survival3, and experimental studies have demonstrated a causal relationship between neutrophils and metastasis4,5. However, the cancer-cell-intrinsic mechanisms that dictate the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Here, using a panel of 16 distinct genetically engineered mouse models for breast cancer, we uncover a role for cancer-cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, loss of p53 in cancer cells induced the secretion of WNT ligands that stimulate tumour-associated macrophages to produce IL-1, thus driving systemic inflammation. Pharmacological and genetic blockade of WNT secretion in p53-null cancer cells reverses macrophage production of IL-1 and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a mechanistic link between the loss of p53 in cancer cells, secretion of WNT ligands and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for patients with cancer.

DOI: 10.1038/s41586-019-1450-6

Source:https://www.nature.com/articles/s41586-019-1450-6