Complex formation between platelet-derived growth factor receptor β and transforming growth factor β receptor regulates the differentiation of mesenchymal stem cells into cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) have recently gained attention as potent targets in cancer therapy because they are a crucial component of the tumor microenvironment and promote the growth and invasion of cancer cells. CAFs differentiate from fibroblasts, mesenchymal stem cells (MSCs), epithelial cells, and other cell types in response to transforming growth factor β (TGFβ) stimulation. The drugs tranilast, imatinib, and pirfenidone reportedly inhibit the differentiation of such cells into CAFs; however, it is unclear how they regulate TGFβ signaling. Here, we differentiated MSCs into CAFs in vitro and investigated which drugs suppressed this differentiation. Based on these results, we focused on platelet-derived growth factor (PDGF) receptor β (PDGFRβ) as a key molecule in the initiation of TGFβ signaling. PDGFRβ transmitted TGFβ signaling in MSCs by forming a complex with TGFβ receptor (TGFβR) independently of stimulation with its well-known ligand PDGF. Inhibitors of the differentiation of MSCs into CAFs attenuated complex formation between PDGFRβ and TGFβR. Moreover, PDGF stimulated PDGFRβ to a lesser extent in CAFs than in MSCs. This study indicates that PDGFRβ and TGFβ-TGFβR signaling cooperatively promote the differentiation of MSCs into CAFs in tumor microenvironments independently of canonical PDGF-PDGFR signaling. We propose that blockade of the interaction between PDGFRβ and TGFβR is a potential strategy to prevent TGFβ-mediated differentiation of MSCs into CAFs.