Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFb signaling

Abstract

A particularly important tumor microenvironment relationship exists between cancer cells and surrounding stromal cells. Fibroblasts, in response to cancer cells, become activated and exhibit myofibroblastic characteristics that favor invasive growth and metastasis. However, the mechanism by which cancer cells promote activation of healthy fibroblasts into cancer-associated fibroblasts (CAF) is still not well understood. Exosomes are nanometer-sized vesicles that shuttle proteins and nucleic acids between cells to establish intercellular communication. Here, bladder cancer–derived exosomes were investigated to determine their role in the activation of healthy primary vesical fibroblasts. Exosomes released by bladder cancer cells are internalized by fibroblasts and promoted the proliferation and expression of CAF markers. In addition, cancer cell–derived exosomes contain TGFb and in exosome-induced CAFs SMAD-dependent signaling is activated. Furthermore, TGFb inhibitors attenuated CAF marker expression in healthy fibroblasts. Therefore, these data demonstrate that bladder cancer cells trigger the differentiation of fibroblasts to CAFs by exosomes-mediated TGFb transfer and SMAD pathway activation. Finally, exosomal TGFb localized inside the vesicle and contributes 53.4% to 86.3% of the total TGFb present in the cancer cell supernatant. This study highlights a new function for bladder cancer exosomes as novel modulators of stromal cell differentiation. Implication: This study identifies exosomal TGFb as new molecular mechanism involved in cancer-associated fibroblast activation.