循环肿瘤细胞在胆管癌侵袭转移中的作用机制研究进展及展望

doi:10.19401/j.cnki.1007-3639.2025.10.008

摘要/Abstract

摘要：

胆管癌作为一种侵袭性强且预后较差的恶性肿瘤，其转移机制复杂，亟待深入研究。循环肿瘤细胞（circulating tumor cell，CTC）作为从原发部位脱落进入血液循环的关键肿瘤细胞类型，对肿瘤的转移具有重要的研究意义。近年来，研究发现，CTC的侵袭性伪足在肿瘤细胞迁移和侵袭中发挥了重要作用。其中，在信号转导通路方面的研究进展表现在：Rho家族GTP酶（RhoA、Rac1、Cdc42）分工协同调控伪足收缩力、肌动蛋白分支聚合及导向，磷脂酰肌醇3-激酶（phosphoinositide3-kinase，PI3K）/蛋白激酶B（protein kinase B，AKT）信号转导通路通过激活AKT促进肌动蛋白组装并与Rho家族交叉对话；在分子机制上的研究进展包括：长链非编码RNA通过吸附miRNA等方式调控伪足相关基因表达，基质金属蛋白酶（matrix metalloproteinase，MMP）降解细胞外基质（extracellular matrix，ECM）形成侵袭正反馈；在微环境方面的研究进展包括：癌相关成纤维细胞（cancer-associated fibroblast，CAF）和巨噬细胞分泌的转化生长因子-β（transforming growth factor-beta，TGF-β）、表皮生长因子（epidermal growth factor，EGF）、白细胞介素-6（interleukin-6，IL-6）等细胞因子激活伪足形成信号转导通路，ECM硬度与纤维排列通过机械力传导影响伪足伸展。本文通过对CTC的生物学特性、胆管癌细胞侵袭性伪足的形成机制、胆管癌细胞的转移特征及其临床意义、CTC在胆管癌转移过程中的作用进行综合分析，总结现有研究成果并探讨潜在的治疗靶点，为胆管癌防治研究工作者提供参考。

关键词: 循环肿瘤细胞, 胆管癌, 侵袭性伪足, 转移, 肿瘤微环境

Abstract:

Cholangiocarcinoma, as a malignant tumor with strong invasiveness and poor prognosis, has a complex metastasis mechanism, and urgently needs in-depth research. Circulating tumor cells (CTC), as the key cell type for tumor cells to shed from the primary site and enter the bloodstream, have significant research significance. In recent years, studies have found that the invasive pseudopodia of CTC play a significant role in the migration and invasion of tumor cells. Among them, in terms of signal transduction pathways, the Rho family GTPases (RhoA, Rac1, Cdc42) work in coordination to regulate the contractility of the pseudofoot, the branching polymerization and orientation of actin, and the phosphoinositide3-kinase/protein kinase B (PI3K/AKT) pathway promotes the assembly of actin and cross-communicates with the Rho family by activating AKT. At the molecular mechanism level, long non-coding RNAs regulate the expression of pseudopolypod-related genes by adsorbing miRNAs and other means. Matrix metalloproteinase (MMP) degrades the extracellular matrix (ECM) to form an invasion positive feedback. In terms of the microenvironment, cancer-associated fibroblast (CAF) and the cytokines such as transforming growth factor-β (TGF-β) secreted by macrophages, epidermal growth factor (EGF), and interleukin-6 (IL-6) activate pseudopodia to form signal transduction pathways. ECM hardness and fiber arrangement affect the extension direction of pseudopodia through mechanical force conduction. This article conducted a comprehensive analysis of the biological characteristics of CTC, the formation mechanism of invasive pseudopodia in cholangiocarcinoma, the metastatic features of cholangiocarcinoma cells and their clinical significance, as well as the role of CTC in the metastatic process of cholangiocarcinoma, in order to summarize the existing research results, explore potential therapeutic targets and future research directions, and provide new ideas for the clinical treatment of cholangiocarcinoma.

Key words: Circulating tumor cells, Cholangiocarcinoma, Invasive pseudopodia, Metastasis, Tumor microenvironment

中图分类号:

R735.8

俞雪, 沈天皓, 周诚, 刘雨, 蒋霆辉, 李炜, 朱永强, 刘艳. 循环肿瘤细胞在胆管癌侵袭转移中的作用机制研究进展及展望[J]. 中国癌症杂志, 2025, 35(10): 952-958.

YU Xue, SHEN Tianhao, ZHOU Cheng, LIU Yu, JIANG Tinghui, LI Wei, ZHU Yongqiang, LIU Yan. Research progress and prospects on the mechanisms of circulating tumor cells in the invasion and metastasis of cholangiocarcinoma[J]. China Oncology, 2025, 35(10): 952-958.

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Research direction	Classification	Mechanism and function	Reference
Signal pathway	Rho family GTP enzymes	RhoA, Rac1 and Cdc42 work in coordination and division of labor, respectively regulating the contractility of pseudopodia, the branching polymerization of actin and the guidance of filamentous pseudopodia, forming a precise regulatory network	[15]
	The PI3K/AKT pathway	By generating PIP3 to activate AKT, it directly promotes actin assembly and cross-communicates with the Rho family, synergistically driving the formation of pseudopodia	[26-27]
Microenvironment interaction	Physical factors	The hardness of ECM and the arrangement of fibers affect the extension direction of pseudopodia, and regulate the migration behavior through mechanical force conduction	[31-32]
	Cytokine	CAFs secrete TGF-β and EGF, and macrophages polarize to produce IL-6, etc., activating pseudopodia to form signaling pathways	[33-34]
Molecular mechanism	Key protein	Cortactin stabilizes the actin network and enhances the structural stability of pseudopodia. MMPs degrade the extracellular ECM, forming an invasive positive feedback	[42]
	LncRNA	Indirectly promote the synthesis of pseudopod-related proteins by adsorbing miRNAs or regulating gene expression	[43]