Liu Yaqin, Ma Peng, Liu Dongdong, Liu Yongzhu, Ran Ziwei, Yang Lunhao, Xu Lingqing, Yin Weiguo, Chen Fu, Li Linhai, Lu Yang
Department of Laboratory Medicine, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, PR China.
Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, PR China.
J Infect. 2025 Aug;91(2):106532. doi: 10.1016/j.jinf.2025.106532. Epub 2025 Jun 11.
Intratumoral bacteria have been identified as prevalent in various solid tumors, playing a significant role in tumor progression. Lymph node metastasis is a major clinical feature and the primary cause of mortality in cervical cancer (CC). However, the effect of intratumoral bacteria on lymphatic node metastasis in CC remains unclear.
This study employed 16S rDNA sequencing and targeted bacterial culture to investigate the distribution of intratumoral bacteria in human CC tissues. The identified Gram-negative bacteria, including Escherichia coli (E. coli), Prevotella bivia (P. bivia), and Fusobacterium nucleatum (F. nucleatum), were isolated, and their roles in metastasis were examined using in vitro transwell and capillary tube formation assays on human lymphatic endothelial cells (HLEC). The signaling pathways involved in metastasis were assessed by examining TLR4/MAPK activation and the expression of prometastatic factors EFNA1 and EDN2. In vivo studies using a mouse footpad tumorigenesis model were also conducted to observe the effect of LPS, which was extracted from these three gram-negative intratumoral bacteria and E. coli on lymph node metastasis.
A higher abundance of Gram-negative bacteria, especially in metastatic CC tissues, was observed. E. coli, P. bivia, and F. nucleatum enhanced capillary tube formation in lymphatic endothelial cells and facilitated metastasis of uninfected tumor cells through paracrine signaling. These bacteria activated the TLR4/MAPK signaling pathway via lipopolysaccharide (LPS), leading to the upregulation of prometastatic factors EFNA1 and EDN2. Knockdown of EFNA1 and EDN2 attenuated the bacteria-induced metastasis, whereas overexpression of these factors mimicked the effects of bacterial infection. In vivo, LPS, which was extracted from E. coli, P. bivia, and F. nucleatum and live E. coli promoted lymph node metastasis, with elevated LPS levels and MAPK-EFNA1/EDN2 expression observed in infected mice compared to controls.
The study suggests that Gram-negative bacteria, particularly E. coli, P. bivia, and F. nucleatum, play a causal role in exacerbating lymph node metastasis in CC. These findings highlight the potential of targeting these bacteria and their associated signaling pathways as therapeutic strategies to improve clinical outcomes in CC patients.
肿瘤内细菌已被证实普遍存在于各种实体瘤中，在肿瘤进展中发挥重要作用。淋巴结转移是宫颈癌（CC）的主要临床特征和死亡的主要原因。然而，肿瘤内细菌对CC淋巴结转移的影响仍不清楚。
本研究采用16S rDNA测序和靶向细菌培养来研究人CC组织中肿瘤内细菌的分布。分离出已鉴定的革兰氏阴性菌，包括大肠杆菌（E. coli）、二路普雷沃菌（P. bivia）和具核梭杆菌（F. nucleatum），并使用体外transwell和毛细管形成试验在人淋巴管内皮细胞（HLEC）上检测它们在转移中的作用。通过检测TLR4/MAPK激活以及促转移因子EFNA1和EDN2的表达来评估参与转移的信号通路。还使用小鼠足垫肿瘤发生模型进行体内研究，以观察从这三种革兰氏阴性肿瘤内细菌和大肠杆菌中提取的脂多糖（LPS）对淋巴结转移的影响。
观察到革兰氏阴性菌丰度较高，尤其是在转移性CC组织中。大肠杆菌、二路普雷沃菌和具核梭杆菌增强了淋巴管内皮细胞中的毛细管形成，并通过旁分泌信号促进未感染肿瘤细胞的转移。这些细菌通过脂多糖（LPS）激活TLR4/MAPK信号通路，导致促转移因子EFNA1和EDN2上调。敲低EFNA1和EDN2可减弱细菌诱导的转移，而这些因子的过表达则模拟了细菌感染的效果。在体内，从大肠杆菌、二路普雷沃菌和具核梭杆菌中提取的LPS以及活大肠杆菌促进了淋巴结转移，与对照组相比，感染小鼠中LPS水平和MAPK-EFNA1/EDN2表达升高。
该研究表明革兰氏阴性菌，特别是大肠杆菌、二路普雷沃菌和具核梭杆菌，在加剧CC淋巴结转移中起因果作用。这些发现突出了将这些细菌及其相关信号通路作为改善CC患者临床结局的治疗策略的潜力。
