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周细胞通过调节肿瘤局部血管张力和血流动力学促进转移。

Pericytes promote metastasis by regulating tumor local vascular tone and hemodynamics.

作者信息

Li Xiaobo, Yan Sishan, Wu Xiaoyu, Miao Qun, Zhang Dong, Mai Wenfeng, Han Shuai, Tang Zhongshun, Ye Mingfang, Zhang Shuo, Wei Ji-An, Pan Jinghua, Huang Dandan, Qiu Shenghui, Zhao Zhan, Zhong Xiaotong, Huang Maohua, Qi Ming, Zhang Junqiu, Wang Chenran, Xie Jingwen, Wang Sheng, Luo Oscar Junhong, Zhang Dongmei, Ye Wencai, Chen Minfeng

机构信息

State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, China.

College of Pharmacy, Jinan University, Guangzhou, China.

出版信息

Nat Commun. 2025 Aug 2;16(1):7115. doi: 10.1038/s41467-025-62475-6.

DOI:10.1038/s41467-025-62475-6
PMID:40753165
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12318036/
Abstract

Hemodynamics are important for survival and extravasation of circulating tumor cells, whereas the effects of hemodynamics on tumor cell intravasation remain mostly unknown. Here, we show that colorectal cancer patients with liver metastasis are characterized by increased diameter and blood flow in the primary tumor compared with non-metastatic patients. A subpopulation of NKX2-3 tumor pericytes (TPCs) in the primary tumor is associated with hematogenous metastasis of patients. Mechanistically, long noncoding RNA NEAT1-enriched extracellular vesicles induce NKX2-3 upregulation in TPCs. NKX2-3 suppresses calcium influx in TPCs via PDE1C/cAMP/PKA signaling axis, inducing tumor vasodilation and increasing blood flux and vascular leakage. Genetic deletion of Nkx2-3 or pharmacological blocking the transcriptional activity of NKX2-3 in TPCs with designed peptide induce tumor local vasoconstriction and decrease blood flow to mitigate tumor metastasis. These findings reveal that TPCs-regulated vasodilation and hemodynamics facilitate tumor metastasis, and provide a potential prognostic marker and therapeutic strategy for tumor metastasis.

摘要

血流动力学对循环肿瘤细胞的存活和外渗很重要，而血流动力学对肿瘤细胞内渗的影响大多仍不清楚。在此，我们表明，与无肝转移的患者相比，发生肝转移的结直肠癌患者的原发肿瘤具有更大的直径和更高的血流量。原发肿瘤中NKX2-3肿瘤周细胞（TPCs）的一个亚群与患者的血行转移有关。从机制上讲，富含长链非编码RNA NEAT1的细胞外囊泡诱导TPCs中NKX2-3上调。NKX2-3通过PDE1C/cAMP/PKA信号轴抑制TPCs中的钙内流，诱导肿瘤血管舒张并增加血流量和血管渗漏。通过基因敲除Nkx2-3或用设计肽在TPCs中阻断NKX2-3的转录活性，可诱导肿瘤局部血管收缩并减少血流量，从而减轻肿瘤转移。这些发现揭示了TPCs调节的血管舒张和血流动力学促进肿瘤转移，并为肿瘤转移提供了潜在的预后标志物和治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/67307af7be2b/41467_2025_62475_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/4468819ab319/41467_2025_62475_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/254809f7ee0d/41467_2025_62475_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/760c496f96fd/41467_2025_62475_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/6fd47765d382/41467_2025_62475_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/89eef6bbb73f/41467_2025_62475_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/76c56bf7e545/41467_2025_62475_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/67307af7be2b/41467_2025_62475_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/4468819ab319/41467_2025_62475_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/254809f7ee0d/41467_2025_62475_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/760c496f96fd/41467_2025_62475_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/6fd47765d382/41467_2025_62475_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/89eef6bbb73f/41467_2025_62475_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/76c56bf7e545/41467_2025_62475_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e928/12318036/67307af7be2b/41467_2025_62475_Fig7_HTML.jpg

相似文献

[1]
Pericytes promote metastasis by regulating tumor local vascular tone and hemodynamics.

Nat Commun. 2025-8-2

[2]
The LncRNA STEAP3-AS1 promotes liver metastasis in colorectal cancer by regulating histone lactylation through chromatin remodelling.

J Exp Clin Cancer Res. 2025-7-15

[3]
Organoid modeling identifies USP3-AS1 as a novel promoter in colorectal cancer liver metastasis through increasing glucose-driven histone lactylation.

Acta Pharmacol Sin. 2025-5

[4]
MicroRNA-6084 orchestrates angiogenesis and liver metastasis in colorectal cancer via extracellular vesicles.

JCI Insight. 2025-6-10

[5]
Exosomal miR-382-5p prevents pre-metastatic niche formation by inhibiting GPR176/GNAS-CXCR1/CXCR2 axis in colorectal cancer liver metastasis.

Cell Signal. 2025-10

[6]
LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53.

Cell Death Dis. 2025-7-7

[7]
mTOR regulates aerobic glycolysis through NEAT1 and nuclear paraspeckle-mediated mechanism in hepatocellular carcinoma.

Theranostics. 2022

[8]
TRIM29 promotes liver metastasis via enhancing hepatic colonization by stabilizing FAM83H to regulate keratin network in colorectal cancer.

Cell Signal. 2025-10

[9]
Targeting LINC02320 prevents colorectal cancer growth via GRB7-dependent inhibition of MAPK signaling pathway.

Cell Mol Biol Lett. 2025-7-21

[10]
Bioengineered Tumor-Derived Extracellular Vehicles Suppressed Colorectal Cancer Liver Metastasis and Bevacizumab Resistance.

Adv Sci (Weinh). 2025-6

本文引用的文献

[1]
Explainable artificial intelligence to identify follicles that optimize clinical outcomes during assisted conception.

Nat Commun. 2025-1-8

[2]
Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer.

Cancer Cell. 2024-7-8

[3]
Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway.

Nat Commun. 2024-2-12

[4]
Targeting FAP-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis.

Acta Pharm Sin B. 2024-2

[5]
TCAF2 in Pericytes Promotes Colorectal Cancer Liver Metastasis via Inhibiting Cold-Sensing TRPM8 Channel.

Adv Sci (Weinh). 2023-10

[6]
Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy.

Leukemia. 2023-6

[7]
Metastasis.

Cell. 2023-4-13

[8]
Novel TCF21 pericyte subpopulation promotes colorectal cancer metastasis by remodelling perivascular matrix.

Gut. 2023-4

[9]
Hypoxia as a regulator of tumor stroma and metastasis.

Am J Physiol Cell Physiol. 2023-1-1

[10]
Hyperoxia evokes pericyte-mediated capillary constriction.

J Cereb Blood Flow Metab. 2022-11

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