Speaker
Description
Background: The hepatocellular carcinoma (HCC) microenvironment is characterized by aberrant vasculature, which drives therapeutic resistance and poor prognosis. Vascular normalization strategies can restructure tumor vessels and improve immune infiltration. To date, whether and how a high-fat diet (HFD) modulates tumor vascular function in HCC remains unclear.
Methods: We established orthotopic hepatic transplantation models and two spontaneous HCC models via hydrodynamic injection of plasmids targeting Trp53 knockout or Ctnnb1 activation. Mice were fed a normal diet (ND) or HFD. Tumor burden, metastasis, and vascular phenotypes were evaluated. Microvessel density, pericyte coverage, and CD8⁺ T cell infiltration were assessed via immunofluorescence and immunohistochemistry. In vitro, liver sinusoidal endothelial cells (LSECs) and human brain microvascular endothelial cells (HBMECs) were treated with palmitic acid (PA), the core component of HFD, to examine proliferation, migration, and tube formation.
Results: In xenograft HCC models, HFD suppressed tumor growth and metastasis, accompanied by decreased microvessel density and branching, increased pericyte coverage, and enhanced CD8⁺ T cell infiltration. In spontaneous HCC models, no significant alterations were observed in Trp53 knockout mice between ND and HFD groups, whereas a pro-tumorigenic trend emerged in Ctnnb1-activated mice in the HFD group. In vitro, PA inhibited aberrant endothelial activation, suppressed LSEC and HBMEC proliferation, migration, and tube formation, and upregulated adhesion molecules and chemokines, collectively improving vascular function.
Conclusion: These findings demonstrate that HFD, via its effector PA, directly inhibits endothelial activation and induces tumor vascular normalization in a stage-dependent manner, providing a theoretical foundation for precision dietary intervention in HCC.
