期刊
STEM CELLS AND DEVELOPMENT
卷 31, 期 13-14, 页码 383-394出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/scd.2022.0088
关键词
regorafenib; cancer-associated fibroblasts; apoptosis; macrophage infiltration
资金
- National Key R&D Program of China [2016YFA0101000, 2016YFA 0101003, 2020YFA0113000, 2020YFA0113001]
- National Natural Science Foundation of China [81971324, 81902848]
- Key R&D Project of Guangdong Province [2021B0909060001, 2021JC0103]
- 111 Project [B18007]
Regorafenib inhibits proliferation and induces apoptosis of gastrointestinal cancer-associated fibroblasts (CAFs) by suppressing the phosphorylation of AKT. It also affects macrophage infiltration in tumor tissues by reducing the proportion of CAFs.
Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and are essential for tumorigenesis and development. Regorafenib is a multikinase inhibitor that targets CAFs and suppresses tumor growth. In this study, we investigated the effects of regorafenib on gastrointestinal CAFs and the underlying molecular mechanisms. First, we established two in vivo tumor models, the cancer cell line HCT116 with and without mesenchymal stem cells (MSCs), and treated them with regorafenib. We found that application of regorafenib potently impaired tumor growth, an effect that was more pronounced in tumors with a high stromal ratio, thus demonstrating that regorafenib can inhibit CAF proliferation and induce CAF apoptosis in vivo. Moreover, we showed that regorafenib affected macrophage infiltration by reducing the proportion of CAFs in tumors. Second, we induced MSCs into CAFs with exosomes to establish an in vitro model. Then, we used 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt and flow cytometry to detect the effects of regorafenib on proliferation and apoptosis of CAFs and western blot to determine the expression level of apoptosis-related proteins. We found that regorafenib inhibited proliferation of CAFs and induced apoptosis in CAFs in vitro. Furthermore, western blot results showed that regorafenib downregulated the expression of B cell lymphoma-2 (Bcl-2) and concurrently upregulated the expression of Bcl-2-associated X (Bax), and regorafenib inhibited the phosphorylation pathway of AKT in CAFs. In conclusion, our results provide a model in which regorafenib induces CAF apoptosis by inhibiting the phosphorylation of AKT and regorafenib affects macrophage infiltration by reducing the proportion of CAFs in tumor tissues.
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