Endothelial Cells Contribute to the Immune-Vascular Milieu Characterizing VETC+ HCC.
9 affiliations
- 1Pathology Unit, IRCCS Humanitas Research Hospital, Milan, Italy.
- 2Department of Biomedical Sciences, Humanitas University, Milan, Italy.
- 3Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy.
- 4Hepatobiliary Immunopathology Lab, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
- 5Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Rozzano, Italy.
- 6Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy.
- 7Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Rozzano, Italy.
- 8Hepatobiliary Unit, Department of Minimally Invasive General and Oncologic Surgery, Humanitas Gavazzeni University Hospital, Bergamo, Italy.
- 9Department of Electrical Engineering and Information Technologies, University of Naples "Federico II", Naples, Italy.
Abstract
Introduction
Vessel encapsulating tumor cluster (VETC) defines a distinct vascular phenotype of hepatocellular carcinoma (HCC), characterized by tumor nests fully encased within a continuous endothelial lining. This architecture correlates with poor prognosis and enhanced sensitivity to anti-angiogenic therapies. To dissect the morphological, phenotypical, molecular, and functional programs that define VETC-associated ECs in HCC and to identify endothelial pathways potentially driving VETC vascular organization and tumor progression.Methods
Biological samples (blood, plasma, Peripheral blood mononuclear cells, and tissue) were collected from VETC+ and VETC- HCCs. Quantitative tissue imaging was integrated with EC-specific molecular profiling. Vascular architecture was assessed on whole-slide images, and purified tumor ECs underwent targeted and transcriptome-wide gene expression analyses.Results
ECs from both VETC+ and VETC- HCCs lacked pro-growth and anti-apoptotic features. VETC+ ECs show overexpression of pro-angiogenic and immune-modulatory factors, in particular vascular endothelial growth factor alpha, FGF and IL10, and a specific gene signature involved in metabolic reprogramming, increased trafficking and migratory capacity. VETC+ transcriptional phenotype is driven by a coordinated hepatic xenobiotic-sensing network in which HNF4A and HNF1A provide the dominant regulatory architecture, while NFE2L2 contributes a distinct regulatory layer governing the antioxidant response elements-dependent arm of the xenobiotic and oxidative-stress response.Conclusion
VETC+ ECs actively shape the HCC microenvironment through the release of angiogenic and immunomodulatory cues. These findings support the existence of a specialized angiocrine program in VETC+ HCC.
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BibTeX
@article{durante2026endothelial,
title = {{Endothelial Cells Contribute to the Immune-Vascular Milieu Characterizing VETC+ HCC.}},
author = {Barbara Durante and Simone Zanella and Francesco de Napoli and Beatrice Esposito and Camilla De Carlo and Reha Akpinar and Cristina Richichi and Francesca Lazzaroni and Barbara Franceschini and Cristiana Soldani and Fabio Grizzi and Fabio Pasqualini and Ana Lleo and Guido Torzilli and Fabio Procopio and Luca Viganò and Salvatore Piscuoglio and Charlotte K Y Ng and Federica Airi and Elvezia Paraboschi and Ines Simeone and Luca Di Tommaso},
journal = {Liver cancer},
year = {2026},
month = oct,
doi = {10.1159/lic/admag014},
url = {https://europepmc.org/article/MED/42924056},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Endothelial Cells Contribute to the Immune-Vascular Milieu Characterizing VETC+ HCC.
AU - Barbara Durante
AU - Simone Zanella
AU - Francesco de Napoli
AU - Beatrice Esposito
AU - Camilla De Carlo
AU - Reha Akpinar
AU - Cristina Richichi
AU - Francesca Lazzaroni
AU - Barbara Franceschini
AU - Cristiana Soldani
AU - Fabio Grizzi
AU - Fabio Pasqualini
AU - Ana Lleo
AU - Guido Torzilli
AU - Fabio Procopio
AU - Luca Viganò
AU - Salvatore Piscuoglio
AU - Charlotte K Y Ng
AU - Federica Airi
AU - Elvezia Paraboschi
AU - Ines Simeone
AU - Luca Di Tommaso
PY - 2026
DA - 2026/10/01
JO - Liver cancer
DO - 10.1159/lic/admag014
UR - https://europepmc.org/article/MED/42924056
AB - Introduction Vessel encapsulating tumor cluster (VETC) defines a distinct vascular phenotype of hepatocellular carcinoma (HCC), characterized by tumor nests fully encased within a continuous endothelial lining. This architecture correlates with poor prognosis and enhanced sensitivity to anti-angiogenic therapies. To dissect the morphological, phenotypical, molecular, and functional programs that define VETC-associated ECs in HCC and to identify endothelial pathways potentially driving VETC vascular organization and tumor progression.Methods Biological samples (blood, plasma, Peripheral blood mononuclear cells, and tissue) were collected from VETC+ and VETC- HCCs. Quantitative tissue imaging was integrated with EC-specific molecular profiling. Vascular architecture was assessed on whole-slide images, and purified tumor ECs underwent targeted and transcriptome-wide gene expression analyses.Results ECs from both VETC+ and VETC- HCCs lacked pro-growth and anti-apoptotic features. VETC+ ECs show overexpression of pro-angiogenic and immune-modulatory factors, in particular vascular endothelial growth factor alpha, FGF and IL10, and a specific gene signature involved in metabolic reprogramming, increased trafficking and migratory capacity. VETC+ transcriptional phenotype is driven by a coordinated hepatic xenobiotic-sensing network in which HNF4A and HNF1A provide the dominant regulatory architecture, while NFE2L2 contributes a distinct regulatory layer governing the antioxidant response elements-dependent arm of the xenobiotic and oxidative-stress response.Conclusion VETC+ ECs actively shape the HCC microenvironment through the release of angiogenic and immunomodulatory cues. These findings support the existence of a specialized angiocrine program in VETC+ HCC.
SN - 2235-1795
SN - 1664-5553
ER -