The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β
Transforming growth factor-β (TGF-β) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-β promotes cancer cell migration, invasion, and proliferation. Pirfenidone (5-methyl-1-phenyl-2(1 H)-pyridone, PFD), an approved drug fo...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | http://dx.doi.org/10.1080/15384047.2022.2035629 |
| _version_ | 1797404046831648768 |
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| author | Gang Wang Xiaowan Zhou Zengli Guo Nan Huang Juan Li Yanfang Lv Lulu Han Wei Zheng Dandan Xu Dafei Chai Huizhong Li Liantao Li Junnian Zheng |
| author_facet | Gang Wang Xiaowan Zhou Zengli Guo Nan Huang Juan Li Yanfang Lv Lulu Han Wei Zheng Dandan Xu Dafei Chai Huizhong Li Liantao Li Junnian Zheng |
| author_sort | Gang Wang |
| collection | DOAJ |
| description | Transforming growth factor-β (TGF-β) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-β promotes cancer cell migration, invasion, and proliferation. Pirfenidone (5-methyl-1-phenyl-2(1 H)-pyridone, PFD), an approved drug for treating pulmonary and renal fibrosis, is a potent TGF-β inhibitor and found reduced incidence of lung cancer and alleviated renal function decline. However, whether PFD plays a role in controlling renal cancer progression is largely unknown. In the present study, we demonstrated that high TGF-β1 expression was negatively associated with ten-year overall survival of patients with renal cancer. Functionally, blockade of TGF-β signaling with PFD significantly suppressed the progression of renal cancer in a murine model. Mechanistically, we revealed that PFD significantly decreased the expression and secretion of TGF-β both in vitro and in vivo tumor mouse model, which further prevented TGF-β-induced EMT and thus cell proliferation, migration, and invasion. Importantly, the downregulation of TGF-β upon PFD treatment shaped the immunosuppressive tumor microenvironment by limiting the recruitment of tumor-infiltrating MDSCs. Therefore, our study demonstrated that PFD prevents renal cancer progression by inhibiting TGF-β production of cancer cells and downstream signaling pathway, which might be presented as a therapeutic adjuvant for renal cancer. |
| first_indexed | 2024-03-09T02:47:26Z |
| format | Article |
| id | doaj.art-73b030e57dbc4d289c244bb1a9138104 |
| institution | Directory Open Access Journal |
| issn | 1538-4047 1555-8576 |
| language | English |
| last_indexed | 2024-03-09T02:47:26Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj.art-73b030e57dbc4d289c244bb1a91381042023-12-05T15:58:13ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762022-12-0123115016210.1080/15384047.2022.20356292035629The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-βGang Wang0Xiaowan Zhou1Zengli Guo2Nan Huang3Juan Li4Yanfang Lv5Lulu Han6Wei Zheng7Dandan Xu8Dafei Chai9Huizhong Li10Liantao Li11Junnian Zheng12Cancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCancer Institute, Xuzhou Medical UniversityCenter of Clinical Oncology, the Affiliated Hospital of Xuzhou Medical UniversityTransforming growth factor-β (TGF-β) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-β promotes cancer cell migration, invasion, and proliferation. Pirfenidone (5-methyl-1-phenyl-2(1 H)-pyridone, PFD), an approved drug for treating pulmonary and renal fibrosis, is a potent TGF-β inhibitor and found reduced incidence of lung cancer and alleviated renal function decline. However, whether PFD plays a role in controlling renal cancer progression is largely unknown. In the present study, we demonstrated that high TGF-β1 expression was negatively associated with ten-year overall survival of patients with renal cancer. Functionally, blockade of TGF-β signaling with PFD significantly suppressed the progression of renal cancer in a murine model. Mechanistically, we revealed that PFD significantly decreased the expression and secretion of TGF-β both in vitro and in vivo tumor mouse model, which further prevented TGF-β-induced EMT and thus cell proliferation, migration, and invasion. Importantly, the downregulation of TGF-β upon PFD treatment shaped the immunosuppressive tumor microenvironment by limiting the recruitment of tumor-infiltrating MDSCs. Therefore, our study demonstrated that PFD prevents renal cancer progression by inhibiting TGF-β production of cancer cells and downstream signaling pathway, which might be presented as a therapeutic adjuvant for renal cancer.http://dx.doi.org/10.1080/15384047.2022.2035629pirfenidonetgf-βrenal cell carcinomaepithelial-to-mesenchymal transitiontumor microenvironment (tme)myeloid-derived suppressor cells (mdsc) |
| spellingShingle | Gang Wang Xiaowan Zhou Zengli Guo Nan Huang Juan Li Yanfang Lv Lulu Han Wei Zheng Dandan Xu Dafei Chai Huizhong Li Liantao Li Junnian Zheng The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β Cancer Biology & Therapy pirfenidone tgf-β renal cell carcinoma epithelial-to-mesenchymal transition tumor microenvironment (tme) myeloid-derived suppressor cells (mdsc) |
| title | The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β |
| title_full | The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β |
| title_fullStr | The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β |
| title_full_unstemmed | The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β |
| title_short | The Anti-fibrosis drug Pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine TGF-β |
| title_sort | anti fibrosis drug pirfenidone modifies the immunosuppressive tumor microenvironment and prevents the progression of renal cell carcinoma by inhibiting tumor autocrine tgf β |
| topic | pirfenidone tgf-β renal cell carcinoma epithelial-to-mesenchymal transition tumor microenvironment (tme) myeloid-derived suppressor cells (mdsc) |
| url | http://dx.doi.org/10.1080/15384047.2022.2035629 |
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