Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), München, Germany.
Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Carcinogenesis. 2021 Apr 17;42(3):405-413. doi: 10.1093/carcin/bgaa109.
Chronic inflammation induces Barrett's Esophagus (BE) which can advance to esophageal adenocarcinoma. Elevated levels of interleukin (IL)-1b, IL-6 and IL-8 together with activated nuclear factor-kappaB (NF-κB), have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells contains myofibroblasts (MFs) that express aSMA and Vimentin. As we observed that increased NF-κB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-κB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-κB signaling in MFs, we crossed L2-IL-1B mice to tamoxifen inducible Vim-Cre (Vim-CreTm) mice and floxed RelA (p65fl/fl) mice to specifically eliminate NF-κB signaling in MF (IL-1b.Vim-CreTm.p65fl/fl). The interaction of epithelial cells and stromal cells was further analyzed in mouse BE organoids and patient-derived human organoids. Histological scoring of IL-1b.Vim-CreTm.p65fl/fl mice showed a significantly attenuated phenotype compared with L2-IL-1B mice, with mild inflammation, decreased metaplasia and no dysplasia. This correlated with decreased proliferation and increased differentiation in cardia tissue of IL-1b.Vim-CreTm.p65fl/fl compared with L2-IL-1B mice. Distinct changes of cytokines and chemokines within the local microenvironment in IL-1b.Vim-CreTm.p65fl/fl mice reflected the histopathological abrogated phenotype. Co-cultured NF-κB inhibitor treated MF with mouse BE organoids demonstrated NF-κB-dependent growth and migration. MFs are essential to form an inflammatory and procarcinogenic microenvironment and NF-κB signaling in stromal cells emerges as an important driver of esophageal carcinogenesis. Our data suggest anti-inflammatory approaches as preventive strategies during surveillance of BE patients.
慢性炎症可引发 Barrett 食管（BE），进而发展为食管腺癌。研究发现，白细胞介素（IL）-1b、IL-6 和 IL-8 水平升高以及核因子-κB（NF-κB）的激活，是肿瘤发生的重要介质。除了癌细胞和浸润免疫细胞外，炎症微环境还包含表达 aSMA 和波形蛋白的肌成纤维细胞（MFs）。由于我们观察到 NF-κB 激活和炎症的增加与 MF 募集的增加和加速表型相关，因此我们在此分析 NF-κB 在我们的 L2-IL-1B 小鼠模型中食管癌变过程中对 MF 的作用。为了分析 NF-κB 信号在 MF 中的作用，我们将 L2-IL-1B 小鼠与他莫昔芬诱导的 Vim-Cre（Vim-CreTm）小鼠和 floxedRelA（p65fl/fl）小鼠杂交，以特异性消除 MF 中的 NF-κB 信号（IL-1b.Vim-CreTm.p65fl/fl）。进一步分析了小鼠 BE 类器官和患者来源的人类类器官中上皮细胞和基质细胞的相互作用。与 L2-IL-1B 小鼠相比，IL-1b.Vim-CreTm.p65fl/fl 小鼠的组织学评分显示出明显减轻的表型，炎症较轻，化生减少，无发育不良。这与 L2-IL-1B 小鼠相比，IL-1b.Vim-CreTm.p65fl/fl 心脏组织中的增殖减少和分化增加有关。IL-1b.Vim-CreTm.p65fl/fl 小鼠局部微环境中细胞因子和趋化因子的明显变化反映了组织病理学上被削弱的表型。与 NF-κB 抑制剂处理的 MF 与小鼠 BE 类器官共培养表明 NF-κB 依赖性生长和迁移。MF 对于形成炎症和促癌微环境是必不可少的，而基质细胞中的 NF-κB 信号传递是食管癌变的重要驱动因素。我们的数据表明，在 BE 患者的监测中，抗炎方法是一种预防策略。
