CXCL3/TGF-β-mediated crosstalk between CAFs and tumor cells augments RCC progression and sunitinib resistance

• Published in: iScience 2024-07, Vol.27 (7), p.110224, Article 110224
• Main Authors: Wang, Yunxia, Ding, Weihong, Hao, Wenjing, Gong, Luyao, Peng, Yeheng, Zhang, Jun, Qian, Zhiyu, Xu, Ke, Cai, Weimin, Gao, Yuan
• Format: Article
• Language: English
• Subjects: Cancer; Microenvironment; Molecular biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110224

Cancer-associated fibroblasts (CAFs) play a significant role in tumor development and treatment failure, yet the precise mechanisms underlying their contribution to renal cell carcinoma (RCC) remains underexplored. This study explored the interaction between CAFs and tumor cells, and related mechanisms. CAFs isolated from tumor tissues promoted the tumor progression and drugs resistance both in vivo and in vitro. Mechanistically, chemokine (C-X-C motif) ligand (CXCL) 3 secreted from CAFs mediated its effects. CXCL3 activated its receptor CXCR2 to active the downstream ERK1/2 signaling pathway, subsequently promoting epithelial-mesenchymal transition and cell stemness. Blocking the crosstalk between CAFs and tumor cells by CXCR2 inhibitor SB225002 attenuated the functions of CAFs. Furthermore, Renca cells facilitated the transformation of normal interstitial fibroblasts (NFs) into CAFs and the expression of CXCL3 through TGF-β-Smad2/3 signaling pathway. In turn, transformed NFs promoted the tumor progression and drug resistance of RCC. These findings may constitute potential therapeutic strategies for RCC treatment. [Display omitted] •CXCL3 derived from CAFs promoted RCC progression and sunitinib resistance•Tumor cells promoted the transformation of NFs and the expression of CXCL3•CXCR2 inhibitor SB225002 blocked the interaction between CAFs and tumor cells Microenvironment; Molecular biology; Cancer