Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Synthetic Analog of Resveratrol Inhibits the Proangiogenic Response of Liver Sinusoidal Cells during Hepatic Metastasis

  • Olaso, Elvira (Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country) ;
  • Benedicto, Aitor (Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country) ;
  • Lopategi, Aritz (Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country) ;
  • Cossio, Fernando P. (Department of Organic Chemistry, School of Sciences, University of the Basque Country) ;
  • Arteta, Beatriz (Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country)
  • Received : 2021.04.01
  • Accepted : 2021.08.14
  • Published : 2022.03.01
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Abstract

We utilized Fas21, a resveratrol analog, to modulate the function of hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) during the angiogenic phase of murine liver metastasis by B16 melanoma and 51b colorectal carcinoma. Preangiogenic micrometastases were treated with Fas21 (1 mg/kg/day) or vehicle during the development of intra-angiogenic tracts. Mice treated with Fas21 showed reduced liver tumor foci in both liver metastasis models. Micrometastases were classified immunohistochemically, as well as according to their position coordinates and connection to local microvasculature. The volume of liver occupied by sinusoidal-type foci, containing infiltrating angiogenic capillaries, decreased by ~50% in Fas21-treated mice compared to vehicle-treated ones in both tumor metastasis models. The volume of portal foci, containing peripheral neoangiogenesis within a discontinuous layer of myofibroblasts, was similar in all experimental groups in both tumor metastasis models, but displayed enhanced necrotic central areas devoid of angiogenesis following Fas21 treatment. As a result, sinusoidal tumors from mice treated with Fas21 showed a 50% reduction in desmin(+)/asma(+) HSCs and CD31(+) vessel density, and a 45% reduction in intrametastatic VEGF mRNA compared with sinusoidal tumors from vehicle-treated mice. Necrotic portal metastases increased 2-4-fold in treated mice. In vitro, Fas21 reduced VEGF secretion by HSCs and 51b cells dose-dependently. Additionally, HSCs migration in response to tumor soluble factors was dose-dependently diminished by Fas21, as was LSEC migration in response to HSCs and tumor soluble factors. Resveratrol analog Fas21 inhibits the proangiogenic response of HSCs and LSECs during the development of murine liver metastasis.

Keywords

Acknowledgement

This work was supported in part by a grant from the Spanish Ministry of Health (04/2785) to EO.

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