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CXCL3/转化生长因子-β介导的癌相关成纤维细胞与肿瘤细胞之间的串扰增强肾细胞癌进展和舒尼替尼耐药性。

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

作者信息

Wang Yunxia, Ding Weihong, Hao Wenjing, Gong Luyao, Peng Yeheng, Zhang Jun, Qian Zhiyu, Xu Ke, Cai Weimin, Gao Yuan

机构信息

School of Pharmacy, Fudan University, Shanghai 201203, China.

Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China.

出版信息

iScience. 2024 Jun 8;27(7):110224. doi: 10.1016/j.isci.2024.110224. eCollection 2024 Jul 19.

DOI:10.1016/j.isci.2024.110224
PMID:39040058
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11261419/
Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/159215c99b92/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/4fd2162df997/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/fd5491a7f4f2/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/8abce800907e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/31450790ff52/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/abe8c9ca4349/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/28ea9aeedca4/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/2b60c966c602/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/159215c99b92/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/4fd2162df997/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/fd5491a7f4f2/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/8abce800907e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/31450790ff52/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/abe8c9ca4349/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/28ea9aeedca4/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/2b60c966c602/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6888/11261419/159215c99b92/gr7.jpg

相似文献

[1]
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[2]
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[6]
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[7]
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[10]
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引用本文的文献

[1]
Integrated analysis of single cell and spatial transcriptomics revealed a metastasis mechanism mediated by fatty acid metabolism in lymph nodes of head and neck cancer.

Front Immunol. 2025-8-13

[2]
Trends and hotspots in targeted therapy resistance research for renal cell carcinoma: a bibliometric and visualization analysis.

Discov Oncol. 2025-6-11

[3]
Revisiting the role of cancer-associated fibroblasts in tumor microenvironment.

Front Immunol. 2025-4-17

[4]
Cancer-associated fibroblasts, tumor and radiotherapy: interactions in the tumor micro-environment.

J Exp Clin Cancer Res. 2024-12-19

[5]
Decoding tumor-fibrosis interplay: mechanisms, impact on progression, and innovative therapeutic strategies.

Front Pharmacol. 2024-10-23

本文引用的文献

[1]
CSF2 upregulates CXCL3 expression in adipocytes to promote metastasis of breast cancer via the FAK signaling pathway.

J Mol Cell Biol. 2023-8-3

[2]
Cancer statistics, 2023.

CA Cancer J Clin. 2023-1

[3]
Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment.

Nat Commun. 2022-11-4

[4]
Cancer-associated fibroblasts promote the stemness and progression of renal cell carcinoma via exosomal miR-181d-5p.

Cell Death Discov. 2022-11-1

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Eur Urol. 2022-11

[6]
Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop.

Int J Biol Sci. 2022

[7]
Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression.

Nat Cancer. 2021-8

[8]
Single-cell transcriptomics reveals a low CD8 T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma.

J Immunother Cancer. 2022-2

[9]
KIAA1199 drives immune suppression to promote colorectal cancer liver metastasis by modulating neutrophil infiltration.

Hepatology. 2022-10

[10]
Exosomes Derived from Cancer-Associated Fibroblasts Regulate Cell Progression in Clear-Cell Renal-Cell Carcinoma.

Nephron. 2022

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