IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.
6 affiliations
- 1Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 2Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 3Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
- 4Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
- 5Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
- 6Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. [email protected].
Abstract
Vascular invasion (VascI) is a critical step in colorectal cancer (CRC) metastasis, but how specific cells in the tumor microenvironment (TME) regulate this process remains unclear, particularly the role of endothelial cells (ECs). Here, we found that vascular invasion is strongly associated with distant metastasis and poor prognosis in CRC patients. Analysis of single-cell RNA sequencing (scRNA-seq) data from 8 colorectal cancer liver metastases (CRLMs), included 4 VascI⁺ CRLMs and 4 VascI⁻ CRLMs, and identified 10 distinct EC subpopulations. Notably, an IGFBP5_tipECs significantly enriched in VascI⁺ CRLMs. High IGFBP5 expression correlated with VascI⁺ status and poor patient prognosis. Functionally, IGFBP5 overexpression (OE) in human umbilical vein endothelial cells (HUVECs) enhanced EC migration, tube formation, barrier disruption, and endothelial-to-mesenchymal transition (EndMT). In co-culture system, IGFBP5-OE ECs promoted malignant epithelial cells (MCs) proliferation, migration, and adhesion, and accelerated the growth of patient-derived CRC organoids. Mechanistically, RNA sequencing nominated ITGB3 as a key downstream effector, with activation of the PI3K/AKT signaling pathway. We confirmed a direct ligand-receptor interaction between EC-derived IGFBP5 and ITGB3 on MCs using multiplex immunofluorescence (mIF), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). This interaction activated PI3K/AKT signaling in MCs, driving aggressive behavior both in vitro and in vivo, an effect that was significantly attenuated by ITGB3 silencing in MCs. Our findings identify IGFBP5-OE ECs as a key driver of VascI and liver metastasis in CRC via the ITGB3/PI3K/AKT axis, highlighting a potential therapeutic target to suppress metastatic progression.
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BibTeX
@article{maimaitiming2026igfbp5,
title = {{IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.}},
author = {Nuersimanguli Maimaitiming and Yiqiao Deng and Huayuan Liu and Junshuai Xue and Chengyao Guo and Xiaomeng Liu and Bingzhi Wang and Xiao Chen and Zhen Huang and Hong Zhao and Jianqiang Cai},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09081-6},
url = {https://europepmc.org/article/MED/42897140},
note = {CC BY},
}
RIS
TY - JOUR
TI - IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.
AU - Nuersimanguli Maimaitiming
AU - Yiqiao Deng
AU - Huayuan Liu
AU - Junshuai Xue
AU - Chengyao Guo
AU - Xiaomeng Liu
AU - Bingzhi Wang
AU - Xiao Chen
AU - Zhen Huang
AU - Hong Zhao
AU - Jianqiang Cai
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09081-6
UR - https://europepmc.org/article/MED/42897140
AB - Vascular invasion (VascI) is a critical step in colorectal cancer (CRC) metastasis, but how specific cells in the tumor microenvironment (TME) regulate this process remains unclear, particularly the role of endothelial cells (ECs). Here, we found that vascular invasion is strongly associated with distant metastasis and poor prognosis in CRC patients. Analysis of single-cell RNA sequencing (scRNA-seq) data from 8 colorectal cancer liver metastases (CRLMs), included 4 VascI⁺ CRLMs and 4 VascI⁻ CRLMs, and identified 10 distinct EC subpopulations. Notably, an IGFBP5_tipECs significantly enriched in VascI⁺ CRLMs. High IGFBP5 expression correlated with VascI⁺ status and poor patient prognosis. Functionally, IGFBP5 overexpression (OE) in human umbilical vein endothelial cells (HUVECs) enhanced EC migration, tube formation, barrier disruption, and endothelial-to-mesenchymal transition (EndMT). In co-culture system, IGFBP5-OE ECs promoted malignant epithelial cells (MCs) proliferation, migration, and adhesion, and accelerated the growth of patient-derived CRC organoids. Mechanistically, RNA sequencing nominated ITGB3 as a key downstream effector, with activation of the PI3K/AKT signaling pathway. We confirmed a direct ligand-receptor interaction between EC-derived IGFBP5 and ITGB3 on MCs using multiplex immunofluorescence (mIF), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). This interaction activated PI3K/AKT signaling in MCs, driving aggressive behavior both in vitro and in vivo, an effect that was significantly attenuated by ITGB3 silencing in MCs. Our findings identify IGFBP5-OE ECs as a key driver of VascI and liver metastasis in CRC via the ITGB3/PI3K/AKT axis, highlighting a potential therapeutic target to suppress metastatic progression.
SN - 2041-4889
ER -