Cancer-Associated Fibroblasts Promote Lymphatic Metastasis in Cholangiocarcinoma via the PDGF-BB/PDGFR-β Mediated Paracrine Signaling Network

被引：12

作者：

Yan, Jian ^{[1
]}

Xiao, Gang ^{[2
,3
]}

Yang, Caini ^{[1
]}

Liu, Qinqin ^{[1
]}

Lv, Cui ^{[4
,5
]}

Yu, Xianhuan ^{[1
]}

Zhou, Ziyu ^{[1
]}

Lin, Shusheng ^{[1
]}

Bai, Zhenhua ^{[1
]}

Lin, Haoming ^{[1
]}

Zhang, Rui ^{[1
]}

Liu, Chao ^{[1
]}

机构：

[1] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Biliary Pancreat Surg, Guangzhou 510120, Peoples R China

[2] South China Univ Technol, Guangzhou Peoples Hosp 1, Dept Thorac Surg, Guangzhou, Peoples R China

[3] South China Univ Technol, Guangzhou Peoples Hosp 1, Ctr Med Res Innovat & Translat, Guangzhou, Peoples R China

[4] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Guangdong Prov Key Lab Malignant Tumor Epigenet &, Guangdong Hong Kong Joint Lab RNA Med, Guangzhou, Guangdong, Peoples R China

[5] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Med Res Ctr, Guangzhou, Peoples R China

来源：

AGING AND DISEASE | 2024年 / 15卷 / 01期

关键词：

Cancer-associated fibroblasts (CAFs); Cholangiocarcinoma (CCA); Platelet-derived growth factor receptor beta (PDGFR-beta); lymphatic endothelial cells (LECs); lymphangiogenesis; MOLECULAR-MECHANISMS; IMATINIB MESYLATE; LYMPHANGIOGENESIS; GROWTH; INVASIVENESS; EXPRESSION; SURVIVAL; ALPHA;

D O I：

10.14336/AD.2023.0420

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

Patients with cholangiocarcinoma (CCA) with lymph node metastasis (LNM) have the worst prognosis, even after complete resection; however, the underlying mechanism remains unclear. Here, we established CAF-derived PDGF-BB as a regulator of LMN in CCA. Proteomics analysis revealed upregulation of PDGF-BB in CAFs derived from patients with CCA with LMN (LN(+)CAFs). Clinically, the expression of CAFPDGF-BB correlated with poor prognosis and increased LMN in patients with CCA, while CAF-secreted PDGFBB enhanced lymphatic endothelial cell (LEC)-mediated lymphangiogenesis and promoted the trans-LEC migration ability of tumor cells. Co-injection of LN(+)CAFs and cancer cells increased tumor growth and LMN in vivo. Mechanistically, CAF-derived PDGF-BB activated its receptor PDGFR-beta and its downstream ERK1/2-JNK signaling pathways in LECs to promote lymphoangiogenesis, while it also upregulated the PDGFR-beta-GSK-P65mediated tumor cell migration. Finally, targeting PDGF-BB/PDGFR-beta or the GSK-P65 signaling axis prohibited CAF- mediated popliteal lymphatic metastasis (PLM) in vivo. Overall, our findings revealed that CAFs promote tumor growth and LMN via a paracrine network, identifying a promising therapeutic target for patients with advanced CCA.

引用

页码：369 / 389

页数：21