Olaso Elvira, Benedicto Aitor, Lopategi Aritz, Cossio Fernando P, Arteta Beatriz
Tumor Microenvironment Group, Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa 48940, Spain.
Department of Organic Chemistry, School of Sciences, University of the Basque Country, Donosti 20018, Spain.
Biomol Ther (Seoul). 2022 Mar 1;30(2):162-169. doi: 10.4062/biomolther.2021.062.
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. , 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.
我们使用白藜芦醇类似物Fas21，来调节B16黑色素瘤和51b结肠直肠癌小鼠肝转移血管生成阶段肝星状细胞（HSCs）和肝窦内皮细胞（LSECs）的功能。在血管生成内通道形成过程中，对血管生成前期微转移灶用Fas21（1mg/kg/天）或赋形剂进行处理。在两种肝转移模型中，用Fas21处理的小鼠肝肿瘤灶均减少。微转移灶通过免疫组织化学进行分类，同时根据其位置坐标以及与局部微血管的连接情况进行分类。在两种肿瘤转移模型中，与赋形剂处理的小鼠相比，Fas21处理的小鼠中含有浸润性血管生成毛细血管的窦状型病灶所占肝脏体积减少了约50%。在两种肿瘤转移模型的所有实验组中，含有肌成纤维细胞不连续层内周缘新生血管生成的门静脉病灶体积相似，但在Fas21处理后，其坏死中央区域增强且无血管生成。结果，与赋形剂处理小鼠的窦状肿瘤相比，Fas21处理小鼠的窦状肿瘤中结蛋白（+）/波形蛋白（+）肝星状细胞和CD31（+）血管密度降低了50%，转移灶内VEGF mRNA降低了45%。处理小鼠中坏死性门静脉转移增加了2至4倍。此外，Fas21剂量依赖性地降低了肝星状细胞和51b细胞的VEGF分泌。另外，Fas21剂量依赖性地减少了肝星状细胞对肿瘤可溶性因子的迁移反应，以及肝窦内皮细胞对肝星状细胞和肿瘤可溶性因子的迁移反应。白藜芦醇类似物Fas21在小鼠肝转移发展过程中抑制肝星状细胞和肝窦内皮细胞的促血管生成反应。
