Inhibition of Hepatic Stellate Cell Activation Suppresses Tumorigenicity of Hepatocellular Carcinoma in Mice.
Inhibition of Hepatic Stellate Cell Activation Suppresses Tumorigenicity of Hepatocellular Carcinoma in Mice.
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DOI：
10.1016/j.ajpath.2021.08.004
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Oh J
中科院分区：
文献类型：
--
作者：
Kang MJ;Lee S;Jung U;Mandal C;Park H;Stetler-Stevenson WG;Kim YS;Moon JW;Park SH;Oh J
肝星状细胞（HSC）向肌成纤维细胞的转分化（或活化）是肝纤维化的关键事件。据报道，肿瘤微环境中活化的HSC促进肿瘤进展。本研究分析了HSC活化抑制剂，视黄醇结合蛋白-白蛋白结构域III融合蛋白（R-III）对HSC促肿瘤功能的影响。虽然从活化的HSC收集的条件培养基增强了肝细胞癌细胞系Hepa-1c 1c 7的迁移、侵袭和增殖，但在用来自R-III暴露的HSC的条件培养基处理的Hepa-1c 1c 7细胞中未观察到这种效果。在皮下肿瘤模型中，与仅移植Hepa-1c 1c 7细胞的小鼠相比，在移植Hepa-1c 1c 7 +HSC的小鼠中形成了更大的具有增加的血管密度的肿瘤。有趣的是，当Hepa-1c 1c 7 + HSC移植小鼠静脉注射R-III时，观察到血管密度降低和肿瘤坏死扩大。在原位肿瘤模型中，HSC的共移植增强了肿瘤生长、血管生成和区域转移，伴随着瘤周淋巴管密度的增加，这被R-III废除。体外研究表明，R-III可影响活化的HSC合成促血管生成因子和抗血管生成因子，这可能是R-III作用的潜在机制。这些发现表明，抑制HSC活化消除了HSC诱导的肿瘤血管生成和生长，这代表了一种有吸引力的治疗策略。
Transdifferentiation (or activation) of hepatic stellate cells (HSCs) to myofibroblasts is a key event in liver fibrosis. Activated HSCs in the tumor microenvironment reportedly promote tumor progression. This study analyzed the effect of an inhibitor of HSC activation, retinol-binding protein–albumin domain III fusion protein (R-III), on protumorigenic functions of HSCs. Although conditioned medium collected from activated HSCs enhanced the migration, invasion, and proliferation of the hepatocellular carcinoma cell line Hepa-1c1c7, this effect was not observed in Hepa-1c1c7 cells treated with conditioned medium from R-III–exposed HSCs. In a subcutaneous tumor model, larger tumors with increased vascular density were formed in mice transplanted with Hepa-1c1c7+HSC than in mice transplanted with Hepa-1c1c7 cells alone. Intriguingly, when Hepa-1c1c7+HSC–transplanted mice were injected intravenously with R-III, a reduction in vascular density and extended tumor necrosis were observed. In an orthotopic tumor model, co-transplantation of HSCs enhanced tumor growth, angiogenesis, and regional metastasis accompanied by increased peritumoral lymphatic vessel density, which was abolished by R-III. In vitro study showed that R-III treatment affected the synthesis of pro-angiogenic and anti-angiogenic factors in activated HSCs, which might be the potential mechanism underlying the R-III effect. These findings suggest that the inhibition of HSC activation abrogates HSC-induced tumor angiogenesis and growth, which represents an attractive therapeutic strategy.
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影响因子：
29.4
作者：
Apte MV;Wilson JS;Lugea A;Pandol SJ
通讯作者：
Pandol SJ
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
24.5
作者：
Kim, N.;Yoo, W.;Oh, J.
通讯作者：
Oh, J.
影响因子：
3.7
作者：
Keeley EC;Mehrad B;Strieter RM
通讯作者：
Strieter RM
影响因子：
3.8
作者：
Byun HO;Lee YK;Kim JM;Yoon G
通讯作者：
Yoon G