An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis

Sep 24, 2026

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Cancer-associated fibroblasts (CAFs) accelerate tumor progression through reciprocal interactions with cancer cells, and tumor-derived extracellular vesicles (EVs) are central mediators of this crosstalk. The mechanisms by which tumor-derived EVs induce a CAF phenotype that drives lymph node (LN) metastasis in bladder cancer (BCa) remain insufficiently defined. This study investigates tumor-derived EV regulation of the CAF phenotype and the molecular pathways governing BCa LN metastasis.

LanguageEnglish

CategoryHealthcare

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Pages23

Reading Time58 min

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Abstract

Background

Methods

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DOI: 10.1002/cac2.12470 ORIGINAL ARTICLE An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis Yuting Li1 Yao Kong4 Hanhao Zheng2, 3 Yuming Luo4 Yue Zhao5 YinaYin1 Le Ai1 Yan Lin2, 3 Mingjie An2, 3 Jian Huang2, 3 Changhao Chen2, 3 1 Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China 2 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China 3 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China 4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, P. R. China 5 Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P. R. China Correspondence Changhao Chen, M.D., Ph.D. Department of Urology, Sun Yat-sen Memorial Hospital, 107 Yanjiangxi Road, Yuexiu District, Guangzhou, Guangdong 510120, P. R. China. Email: [chenchh53@mail.sysu.edu.cn](chenchh53@mail.sysu.edu.cn) Abstract Background: Cancer-associated fibroblasts (CAFs) play a vital role in facilitating tumor progression through extensive reciprocal interplay with cancer cells. Tumor-derived extracellular vesicles (EVs) are the critical mediators involved in the crosstalk between cancer cells and stromal cells, contributing to the Abbreviations: CAFs, Cancer-associated fibroblasts; EVs, extracellular vesicles; LN, lymph node; BCa, bladder cancer; lncRNAs, long non-coding RNAs; PDX, patient-derived xenograft; MIBC, muscle-invasive bladder cancer; TME, tumor microenvironment; NATs, normal adjacent tissues; OS, overall survival; DFS, disease-free survival; ATCC, American Type Culture Collection; RPMI, Roswell Park Memorial Institute; MEM, minimal essential medium; HLECs, human lymphatic endothelial cells; ECM, endothelial cell medium; FBS, fetal bovine serum; CM, culture media; STR, short tandem repeat; RACE, 5’ and 3’ rapid amplification ofcDNA ends; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; α-SMA, alpha-Smooth Muscle Actin; FAP, fibroblast activation protein; PDGFRα, platelet-derived growth factor receptor-α; FSC-A, forward-scatter area; SSC-A, side-scatter area; FACS, fluorescence-activated cell sorting; DTT, dithiothreitol; ROC, receiver operating characteristic; BSA, bovine serum albumin; GFP, green fluorescent protein; IHC, immunohistochemistry; NSG, nonobese diabetic/severe combined immunodeficiency/ interleukin-2r-γ-null; αHGF, neutralizing antibody against hepatocyte growth factor; FRET, fluorescence resonance energy transfer; CD, circular dichroism; TFOs, triplex-forming oligonucleotides; TTS, triplex target sites; TAMRA, tetramethyl-rhodamine; FAM, fluorescein amidite; TCGA, The Cancer Genome Atlas; GEPIA, Gene Expression Profiling Interactive Analysis; hnRNPL, heterogeneous nuclear ribonucleoprotein L; SPSS, Statistical Product and Service Solutions; SD, standard deviations; χ2 test, chi-square test; ANOVA, 1-way analysis of variance; scRNA-seq, single-cell RNA sequencing; LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1; MLD, micro-lymphatic vessel density; ISH, in situ hybridization; FISH, fluorescence in situ hybridization; qRT-PCR, quantitative real-time PCR; siRNA, small interfering RNA; MS, Mass spectrometry; RIP, RNA immunoprecipitation; ChIRP, chromatin isolation by RNA purification; H3K4me3, H3K4 trimethylation; ChIP, chromatin immunoprecipitation; LINC00665KO , LINC00665 knockout; LINC00665WT , LINC00665 wild type; CAFsLINC00665-EVs , LINC00665-induced EVs; IL-6, interleukin 6; IL-8, interleukin 8; Dkk-1, dickkopfWNT signaling pathway inhibitor 1; CXCL10, C-X-C motif chemokine ligand 10; VEGF, vascular endothelial growth factor; ELISA, enzyme-linked immunosorbent assay; GEO, G

FAQs

What study question does the work address?

The study examines how tumor-derived extracellular vesicles regulate the CAF phenotype to drive lymph node metastasis in bladder cancer and investigates the underlying molecular mechanisms.

How were key molecular components identified?

High-throughput sequencing was used to identify crucial long non-coding RNAs (lncRNAs) associated with CAF enrichment in bladder cancer.

What experimental approaches were used to test mechanisms?

In vitro and in vivo assays assessed fibroblast-to-CAF transitions, while chromatin isolation by RNA purification, FRET, cytokine profiling, and patient-derived xenograft (PDX) models explored LINC00665-related pathways.

Sep 24, 2026

Uploaded by Bulrr