Endothelial Cells Contribute to the Immune-Vascular Mileu Characterizing VETC+ HCC

Abstract

Background. 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. Aim. 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. Materials and Methods. Biological samples (blood, plasma, PBMCs, 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 VEGFA, 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 ARE-dependent arm of the xenobiotic and oxidative-stress response. Conclusions. 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.