Elimination of NF-κB signaling in Vimentin+ stromal cells attenuates tumorigenesis in a mouse model of Barrett’s Esophagus

Abstract

Chronic inflammation induces Barrett Esophagus (BE) which can advance to esophageal adenocarcinoma (EAC). Elevated levels of IL-1b, IL-6, and IL-8 together with activated NF-kB, have been identified as important mediators of tumorigenesis. The inflammatory milieu apart from cancer cells and infiltrating immune cells, contains myofibroblasts (MF) that express aSMA and Vimentin. As we observed that increased NF-kB activation and inflammation correlates with increased MF recruitment and an accelerated phenotype we here analyze the role of NF-kB in MF during esophageal carcinogenesis in our L2-IL-1B mouse model. To analyze the effect of NF-kB 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-kB 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 to 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 to 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-kB inhibitor treated MF with mouse BE organoids demonstrated NF-kB dependent growth and migration. MF are essential to form an inflammatory and pro-carcinogenic microenvironment and NF-kB 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.

Telomere shortening accelerates tumor initiation in the L2-IL1B mouse model of Barrett esophagus and emerges as a possible biomarker

“…In the L2-IL-1B mouse model, the chosen time points at 9 and 12 months of represent early stages of the disease. L2-IL-1B mice without further acceleration (such as HFD [ 29 ], bile acid [ 26 ], Notch [ 30 ], IL-8 [ 29 ], NfkB [ 31 ]) develop strong dysplasia consistently only at the age of 15 months.…”

What is new in cancer-associated fibroblast biomarkers?

“…During the progression of esophageal cancer initiated by chronic inflammation, vimentin + α-SMA + myofibroblasts migrate to sites of intestinal metaplasia and dysplasia, and may become an innocent bystander in tumor progression by directly enhancing proliferation of nearby epithelial cells in an NF-κB-dependent manner as well as indirectly by recruiting and polarizing cells of the adaptive and innate immune system toward a tumor-promoting phenotype [ 140 ].…”

The prevalence of coronary atherosclerosis in patients with refractory gastroesophageal reflux disease ready for antireflux surgery

“…A previous study reported that the inflammatory markers IL-6, IL-8, and NF-kappaB were significantly associated with the severity of CAS and associated with BE. [28][29][30] However, further study is still required to investigate whether this is the potential mechanism to correlate BE with CAS.…”