Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
Oncogene. 2020 Apr;39(14):2961-2974. doi: 10.1038/s41388-020-1197-4. Epub 2020 Feb 7.
Cancer-associated fibroblasts (CAFs) play a major role in the progression of stomach cancer, but the related mechanisms are not fully understood. H. pylori infection is recognized as one of the strongest risk factors for gastric carcinoma, but its effects on CAFs remain unknown. We aimed to determine the causative relationship between H. pylori infection in fibroblasts and the promoted cancer pathogenesis and progression in gastric cancer. Primary CAFs and normal activated fibroblasts (NAFs) were generated from gastric cancer patients. Gene signature of H. pylori-infected human stomach fibroblasts was performed using the RNA-seq analysis. Spheroid cell invasion assay and zebrafish cell line-derived xenograft (zCDX) model were introduced to evaluate tumor invasion induced by CAFs. The molecule interactions were determined using the kinetic binding analysis with the Biolayer Interferometry (BLI). Clinical significance and relevance were also assessed using the database analyses. H. pylori infection activated stomach fibroblasts and caused multiple gene alterations, including vascular adhesion molecule 1 (VCAM1). H. pylori infection increased VCAM1 expression in CAFs in gastric carcinoma via activation of JAK/STAT1 signaling pathway, and VCAM1 levels were positively associated with tumor progression and dismal prognosis in stomach cancer patients. Furthermore, CAFs-derived VCAM1 molecularly interacted with integrin αvβ1/5 in gastric cancer cells facilitated tumor invasion in vitro and in vivo. Our results identify a novel mechanism underlying CAFs to promote tumor invasion during H. pylori infection. These studies facilitate us for a better understanding of the molecular process of gastric carcinoma progression, and provide the potential strategies for gastric cancer therapy.
癌相关成纤维细胞 (CAFs) 在胃癌的进展中起着重要作用，但相关机制尚未完全阐明。幽门螺杆菌 (H. pylori) 感染被认为是胃癌最强的危险因素之一，但它对 CAFs 的影响尚不清楚。我们旨在确定 H. pylori 感染成纤维细胞与促进胃癌发病机制和进展之间的因果关系。从胃癌患者中生成原代 CAFs 和正常激活成纤维细胞 (NAFs)。使用 RNA-seq 分析进行 H. pylori 感染人胃成纤维细胞的基因特征分析。采用球体细胞侵袭实验和斑马鱼细胞系衍生的异种移植 (zCDX) 模型评估 CAFs 诱导的肿瘤侵袭。使用动力学结合分析生物层干涉 (BLI) 确定分子相互作用。还使用数据库分析评估了临床意义和相关性。H. pylori 感染激活胃成纤维细胞并导致多种基因改变，包括血管细胞黏附分子 1 (VCAM1)。H. pylori 感染通过激活 JAK/STAT1 信号通路增加 CAFs 中 VCAM1 的表达，并且 VCAM1 水平与胃癌患者的肿瘤进展和预后不良呈正相关。此外，CAFs 衍生的 VCAM1 分子与整合素 αvβ1/5 在胃癌细胞中相互作用，促进体外和体内肿瘤侵袭。我们的研究结果确定了 CAFs 在 H. pylori 感染期间促进肿瘤侵袭的新机制。这些研究使我们更好地理解了胃癌进展的分子过程，并为胃癌治疗提供了潜在的策略。
