美国冷泉港实验室Mikala Egeblad课题组取得一项新突破。他们的论文发现了中性粒细胞导致血管闭塞、肿瘤坏死和转移。相关论文于2025年7月16日发表在《自然》杂志上。

在多种癌症母主题模型中，小组发现肿瘤诱导的Ly6G^HighLy6C^Low中性粒细胞群体在炎症挑战下无法外渗，但比传统的Ly6G^HighLy6C^High中性粒细胞更有效地形成中性粒细胞细胞外陷阱（NETs）。这些“血管限制性”中性粒细胞的存在与小鼠“多形性”坏死结构的出现相关。在多形性坏死的肿瘤中，小组发现血管内中性粒细胞和NET聚集，它们阻塞了肿瘤的脉管系统，导致下游血管床缺氧和坏死。

此外，研究人员发现这些坏死区域附近的癌细胞（即“会阴坏死”区域）经历了上皮细胞到间质细胞的转变，这解释了肿瘤坏死促进转移的矛盾作用。基因或药理学上阻断NET的形成可减少肿瘤坏死和肺转移的程度。通过研究NET驱动血管闭塞、多形性坏死和转移，研究人员证明肿瘤坏死不一定是肿瘤生长的被动副产物，可以阻断肿瘤坏死以减少转移性扩散。

据了解，肿瘤坏死与癌症预后不良有关，被认为是肿瘤生长超过营养供应时被动发生的。然而，这里研究人员报告中性粒细胞积极诱导肿瘤坏死。

附：英文原文

Title: Neutrophils drive vascular occlusion, tumour necrosis and metastasis

Author: Adrover, Jose M., Han, Xiao, Sun, Lijuan, Fujii, Takeo, Sivetz, Nicole, Daler-Plenker, Juliane, Evans, Clary, Peters, Jessica, He, Xue-Yan, Cannon, Courtney D., Ho, Won Jin, Raptis, George, Powers, R. Scott, Egeblad, Mikala

Issue&Volume: 2025-07-16

Abstract: Tumour necrosis is associated with poor prognosis in cancer1,2 and is thought to occur passively when tumour growth outpaces nutrient supply. Here we report, however, that neutrophils actively induce tumour necrosis. In multiple cancer mouse models, we found a tumour-elicited Ly6GHighLy6CLow neutrophil population that was unable to extravasate in response to inflammatory challenges but formed neutrophil extracellular traps (NETs) more efficiently than classical Ly6GHighLy6CHigh neutrophils. The presence of these ‘vascular-restricted’ neutrophils correlated with the appearance of a ‘pleomorphic’ necrotic architecture in mice. In tumours with pleomorphic necrosis, we found intravascular aggregates of neutrophils and NETs that caused occlusion of the tumour vasculature, driving hypoxia and necrosis of downstream vascular beds. Furthermore, we found that cancer cells adjacent to these necrotic regions (that is, in ‘perinecrotic’ areas) underwent epithelial-to-mesenchymal transition, explaining the paradoxical metastasis-enhancing effect of tumour necrosis. Blocking NET formation genetically or pharmacologically reduced the extent of tumour necrosis and lung metastasis. Thus, by showing that NETs drive vascular occlusion, pleomorphic necrosis and metastasis, we demonstrate that tumour necrosis is not necessarily a passive byproduct of tumour growth and that it can be blocked to reduce metastatic spread.

DOI: 10.1038/s41586-025-09278-3

Source: https://www.nature.com/articles/s41586-025-09278-3