Journal
CANCER BIOLOGY & THERAPY
Volume 23, Issue 1, Pages 150-162Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384047.2022.2035629
Keywords
Pirfenidone; TGF-beta; renal cell carcinoma; epithelial-to-mesenchymal transition; tumor microenvironment (TME); myeloid-derived suppressor cells (MDSC)
Categories
Funding
- Jiangsu Provincial Key Research and Development Program [BE2020641, BE2020640]
- Jiangsu Provincial Medical Youth Talent [QNRC2016773]
- National Natural Science Foundation of China [82072814, 81803080, 81871869]
- Natural Science Foundation of Jiangsu Province [BK20161157, BK20180990]
- Xuzhou Science and Technology Plan Project [KC16HG234]
- Jiangsu Provincial Key Medical Discipline, The Project of Invigorating Health Care through Science, Technology and Education [CXTDA2017034, ZDXKA2016014]
- Youth Technology Innovation Team of Xuzhou Medical University [TD202003]
- Key Research Development project of Xuzhou [KC19082]
- Natural Science Key Project of Jiangsu Provincial Education Department [19KJA470001]
- Post graduate Research & Practice Innovation Program of Jiangsu Province [KYCX18_2185]
- Six Talent Peaks Project in Jiangsu Province [WSN-119]
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The study demonstrates that PFD can prevent the progression of renal cancer by inhibiting the production of TGF-beta and its downstream signaling pathway in cancer cells. It also regulates the tumor microenvironment to suppress the recruitment of immunosuppressive cells.
Transforming growth factor-beta (TGF-beta) plays a critical role in regulating cell growth and differentiation. Epithelial to mesenchymal transition (EMT) induced by TGF-beta 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-beta 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-beta expression was negatively associated with ten-year overall survival of patients with renal cancer. Functionally, blockade of TGF-beta 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-beta both in vitro and in vivo tumor mouse model, which further prevented TGF-beta-induced EMT and thus cell proliferation, migration, and invasion. Importantly, the downregulation of TGF-beta 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-beta production of cancer cells and downstream signaling pathway, which might be presented as a therapeutic adjuvant for renal cancer.
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