RHBDF2 in Stromal Fibroblasts Mediates TGF-b Signal and Enhances Cancer Cell Invasion via Intercellular Cross-Talk

Cancer-associated fibroblasts (CAFs) existing in tumor stroma play a crucial role in tumor progression. Here, we show that stromal fibroblasts near cancer cells are likely to display up-regulated RHBDF2 expression caused by chronic stimulation from pro-inflammatory cytokines. RHBDF2 promotes both the cleavage of type I transforming growth factor (TGF)-b receptor, through tumor necrosis factor a converting enzyme activation, and the motility of CAFs upon stimulation with TGF-b1. High-motility CAFs can consequently assist cancer cell invasion. Furthermore, the expression profiles of these cytokines are significantly associated with poor prognosis in gastric cancer (GC) patients. These findings highlight the underlying mechanism whereby cancer cells take advantage of CAFs to acquire invasiveness. Overall design: 11 matched normal and cancer fibroblast cell lines from diffused type gastric cancer and normal samples