Skip to content
DraconiticResearch
Search Sources API
220,595 studies31 sourcesUpdated 45 min ago
Peer-reviewedCC BY-NC-ND 4.0Journal of Translational Medicine

Colorectal cancer-derived IGFBP2 promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation

  • Jing Shang1
  • Qin Yuan2
  • Yuhua Lin3
  • Jiahua Yang2
  • Peihao Yin4,5
  • Wei Li2
5 affiliations
  1. 1Department of Radiology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062 China
  2. 2Department of General Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062 China
  3. 3Department of Respiratory Medicine, Xiamen TCM Hospital Affiliated to Fujian, University of Traditional Chinese Medicine, Xiamen, 361015 China
  4. 4Department of General Surgery, Shanghai Putuo People’s Hospital, Tongji University School of Medicine, Shanghai, 200060 China
  5. 5Shanghai Key Laboratory of Wearable Robotics and Human-Machine Interaction, Shanghai, 201804 China
Read full textDOICite

Abstract

Background: Colorectal cancer (CRC) liver metastasis (LM) is a leading cause of cancer-related death, with pre-metastatic niche (PMN) formation being critical for metastasis. Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in metastatic CRC, but its role in intrahepatic fibrotic PMN formation and CRC-LM remains unclear.

Methods: Bioinformatics analyses and tissue microarray samples were conducted to assess the expression level and prognostic significance of IGFBP2 in CRC patients. After overexpression of IGFBP2, its in vivo metastatic-promoting ability was evaluated by establishing a splenic injection liver metastasis model, while its in vitro malignant properties were assessed via colony formation, proliferation assay, flow cytometry, wound-healing assay and transwell assay. Furthermore, flow cytometry, RT-qPCR and ELISA were used to evaluate the effect of IGFBP2 overexpression on the polarization of intrahepatic macrophages. In addition, Western blot and immunofluorescence were performed to detect the effect of M2-polarized macrophages on hepatic stellate cells (HSCs). Finally, the splenic injection liver metastasis model was treated with CWI1-2 (IGFBP2 inhibitor) or pirfenidone (PFD, a TGF-β signaling modulator), and the therapeutic effects were observed.

Results: We found that IGFBP2 is overexpressed in CRC tissues, correlating with poor prognosis. Meanwhile, IGFBP2 overexpression significantly promotes CRC-LM progression in vivo. Mechanistically, it drives M2 polarization of intrahepatic macrophages to boost TGF-β secretion. Subsequently, TGF-β activates HSCs, elevates the deposition of extracellular matrix (α-SMA, COL1, FN), and ultimately contributes to the development of intrahepatic fibrotic PMN. Notably, CWI-2 or PFD could suppress CRC-LM, with combined treatment showing synergistic effects both in vitro and in vivo.

Conclusions: IGFBP2 is highly expressed in CRC and correlated with patient prognosis. CRC-derived IGFBP2 drives intrahepatic fibrotic PMN formation via intrahepatic macrophages M2 polarization and TGF-β-mediated HSCs activation, which in turn facilitates CRC-LM. Furthermore, selective targeting of the process of intrahepatic PMN formation holds promise as a viable strategy for the prevention and treatment of CRC-LM.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08726-6.

Related

  1. Aberrant CPS1 expression is linked to metabolic alterations and metastatic phenotypes in colorectal cancer liver metastasis
    Qin Xiang, Ming Yang, Xiaoyu Li +7
    Scientific ReportsPeer-reviewedCC BY 4.0Full textOncologyCrossref
  2. Loss of Farnesoid X Receptor promotes colorectal liver metastasis via the GutFXR–FGF15–PPARγ–VEGFα–MDSC axis
    Yan Chen, Yufei Wu, Yu Yang +3
    Molecular MedicinePeer-reviewedCC BY-NC-ND 4.0Full textOncologyPMC
  3. Intracranial metastasis following intrahepatic remission in primary hepatic small cell neuroendocrine carcinoma: a case report
    Jing Cui, Yukai Gao
    Frontiers in medicinePeer-reviewedCC BYFull textGeneral medicineEurope PMC
  4. Distant Cutaneous Metastasis as the First Sign of Recurrence After R0 Resection of Intrahepatic Cholangiocarcinoma: A Case Report.
    Yusuke Takeshita, Kazunori Nojiri, Naoki Maeda +2
    CureusPeer-reviewedCC BYFull textOncologyEurope PMCPMC
  5. OLFM4 promotes intrahepatic cholangiocarcinoma progression through a PKM2-glycolysis-histone lactylation feedback loop.
    Shuochen Liu, Kai Cao, Changan Chen +11
    International journal of biological sciencesPeer-reviewedCC BYFull textSurgery & anaesthesiaEurope PMC

Cite

BibTeXRIS
BibTeX
@article{shang2026colorectal,
  title = {{Colorectal cancer-derived IGFBP2 promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation}},
  author = {Jing Shang and Qin Yuan and Yuhua Lin and Jiahua Yang and Peihao Yin and Wei Li},
  journal = {Journal of Translational Medicine},
  year = {2026},
  month = aug,
  doi = {10.1186/s12967-026-08726-6},
  url = {https://doi.org/10.1186/s12967-026-08726-6},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Colorectal cancer-derived IGFBP2 promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation
AU  - Jing Shang
AU  - Qin Yuan
AU  - Yuhua Lin
AU  - Jiahua Yang
AU  - Peihao Yin
AU  - Wei Li
PY  - 2026
DA  - 2026/08/10
JO  - Journal of Translational Medicine
DO  - 10.1186/s12967-026-08726-6
UR  - https://doi.org/10.1186/s12967-026-08726-6
AB  - Background: Colorectal cancer (CRC) liver metastasis (LM) is a leading cause of cancer-related death, with pre-metastatic niche (PMN) formation being critical for metastasis. Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in metastatic CRC, but its role in intrahepatic fibrotic PMN formation and CRC-LM remains unclear.  Methods: Bioinformatics analyses and tissue microarray samples were conducted to assess the expression level and prognostic significance of IGFBP2 in CRC patients. After overexpression of IGFBP2, its in vivo metastatic-promoting ability was evaluated by establishing a splenic injection liver metastasis model, while its in vitro malignant properties were assessed via colony formation, proliferation assay, flow cytometry, wound-healing assay and transwell assay. Furthermore, flow cytometry, RT-qPCR and ELISA were used to evaluate the effect of IGFBP2 overexpression on the polarization of intrahepatic macrophages. In addition, Western blot and immunofluorescence were performed to detect the effect of M2-polarized macrophages on hepatic stellate cells (HSCs). Finally, the splenic injection liver metastasis model was treated with CWI1-2 (IGFBP2 inhibitor) or pirfenidone (PFD, a TGF-β signaling modulator), and the therapeutic effects were observed.  Results: We found that IGFBP2 is overexpressed in CRC tissues, correlating with poor prognosis. Meanwhile, IGFBP2 overexpression significantly promotes CRC-LM progression in vivo. Mechanistically, it drives M2 polarization of intrahepatic macrophages to boost TGF-β secretion. Subsequently, TGF-β activates HSCs, elevates the deposition of extracellular matrix (α-SMA, COL1, FN), and ultimately contributes to the development of intrahepatic fibrotic PMN. Notably, CWI-2 or PFD could suppress CRC-LM, with combined treatment showing synergistic effects both in vitro and in vivo.  Conclusions: IGFBP2 is highly expressed in CRC and correlated with patient prognosis. CRC-derived IGFBP2 drives intrahepatic fibrotic PMN formation via intrahepatic macrophages M2 polarization and TGF-β-mediated HSCs activation, which in turn facilitates CRC-LM. Furthermore, selective targeting of the process of intrahepatic PMN formation holds promise as a viable strategy for the prevention and treatment of CRC-LM.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08726-6.
SN  - 1479-5876
ER  -