IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment.

摘要: The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component TME, contributing to tumorigenesis by secreting growth factors, modifying extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through unbiased approach, we have established IL-6 mediates cross-talk between cells CAF not only cell growth, but also promoting fibroblast activation. As result, receptor (IL6Rα) downstream effectors offer opportunities for targeted therapy upper-GI cancers. loss suppressed physiologically relevant three-dimensional (3D) organotypic 3D tumoroid models murine esophageal cancer. Tocilizumab, anti-IL6Rα antibody, vivo part via inhibition STAT3 MEK/ERK signaling. Analysis pan-cancer TCGA dataset revealed inverse correlation IL6Rα overexpression patient survival. Therefore, expanded evaluation tocilizumab head neck squamous carcinoma patient-derived xenografts gastric adenocarcinoma xenografts, demonstrating suppression altered ERK1/2 gene signatures. We used small-molecule inhibitors MEK1/2 signaling suppress model demonstrate IL6 is contributor dynamic TME. Our findings provide translational rationale pathways as novel oral-upper-GI cancers.Significance: These interaction cancer-associated through signaling, providing approach target these Cancer Res; 78(17); 4957-70. ©2018 AACR.