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.
Highlights
Tumor tissues are composed of cancer cells and the surrounding microenvironments
Among the various cell types that reportedly give rise to cancerassociated fibroblast (CAF), we focused on mesenchymal stem cell (MSC), which can differentiate into various cell types including osteoblastic cells, adipocytes, muscle cells, and CAFs [25]
No further complex formation between PDGFRβ and TGFβ receptor (TGFβR) was observed when CAFs that had differentiated from ST2 cells in response to transforming growth factor β (TGFβ) were re-stimulated with TGFβ (Figure 5A). These results suggest that the interaction between PDGFRβ and TGFβR is important for initiation of the differentiation of MSCs into CAFs and that this complex is maintained in CAFs
Summary
Tumor tissues are composed of cancer cells and the surrounding microenvironments. Tumor microenvironments contain vascular lymphatic networks, fibroblastic cells, inflammatory immune cells, mesenchymal stem cells (MSCs), and extracellular matrices [1, 2]. Puttini et al investigated the suppressive effects of bosutinib and imatinib on growth of leukemia cells expressing Bcr-Abl, Ba/F3 cells expressing PDGFRβ, and gastrointestinal stromal tumor cells expressing c-KIT, and calculated their IC50 values [26]. They estimated that the IC50 values of imatinib and bosutinib in Ba/F3 cells expressing PDGFRβ are 3.4 and 370 nmol/L, respectively, suggesting that imatinib strongly inhibits PDGFRβ [26]. We hypothesized that PDGFRs, including PDGFRβ, induce differentiation into CAFs in cooperation with TGFβ signaling
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