Wang Yunxia, Ding Weihong, Hao Wenjing, Gong Luyao, Peng Yeheng, Zhang Jun, Qian Zhiyu, Xu Ke, Cai Weimin, Gao Yuan
School of Pharmacy, Fudan University, Shanghai 201203, China.
Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.
iScience. 2024 Jun 8;27(7):110224. doi: 10.1016/j.isci.2024.110224. eCollection 2024 Jul 19.
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 and . 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.
癌症相关成纤维细胞（CAFs）在肿瘤发展和治疗失败中发挥着重要作用，但其对肾细胞癌（RCC）作用的精确机制仍未得到充分探索。本研究探讨了CAFs与肿瘤细胞之间的相互作用及其相关机制。从肿瘤组织中分离出的CAFs促进了肿瘤进展和耐药性。机制上，CAFs分泌的趋化因子（C-X-C基序）配体（CXCL）3介导了其作用。CXCL3激活其受体CXCR2以激活下游ERK1/2信号通路，随后促进上皮-间质转化和细胞干性。通过CXCR2抑制剂SB225002阻断CAFs与肿瘤细胞之间的串扰减弱了CAFs的功能。此外，Renca细胞通过TGF-β-Smad2/3信号通路促进正常间质成纤维细胞（NFs）向CAFs的转化以及CXCL3的表达。反过来，转化后的NFs促进了RCC的肿瘤进展和耐药性。这些发现可能构成RCC治疗的潜在策略。
