Infiltrating Macrophages Induced Stem-cell-like Features Through PI3K/AKT/GSK3β Signaling to Promote Neurofibroma Growth

Inflammation plays an important role in promoting neurofibroma progression, and macrophages are key inflammatory cells in neurofibroma.We attempted to clarify the detailed mechanism of infiltrating macrophages promoting neurofibroma progression.We performed IHC and Western blot assays to detect the expression levels of OCT3/4, Nanog and SOX2 in tissues and cells. A colony/sphere formation assay was used to analyze cell stemness. MTT, colony formation assay and xenograft tumor model were used to detect cell growth. The transwell system was used to examine macrophage infiltration.We demonstrated increased macrophage infiltration in neurofibroma tissues accompanied by increased stem cell-like markers. Moreover, Nf1-mutated SW10 cells possessed a stronger capacity to recruit macrophages, which in turn facilitated neurofibroma growth. Mechanistically, the infiltrating macrophages induced neurofibroma cell stem cell transition by modulating PI3K/AKT/GSK3β signaling, which then enhanced neurofibroma cell viability in vivo and in vitro.Our results revealed a new mechanism of infiltrating macrophages contributing to neurofibroma progression, and targeting this newly identified signaling may help to treat neurofibroma.