Fig. 9

Schematic of the findings of the present study. The TSP-4 secreted by CAFs binds to integrin α2 on the surface of GBC cells, thus activating downstream signaling cascades, including upregulation the phosphorylation of AKT and HSF1(p-AKT: S473 and p-HSF1:S326), which induces nuclear translocation of p-HSF1, and triggers the EMT and cancer stem-like traits. Activated HSF1 signaling further increased the expression and paracrine of TGF-β to induce the transdifferentiation of reactive fibroblasts into CAFs, leading to their recruitment into GBC and increased TSP-4 expression in CAFs