The resistance to therapy and relapse in hepatocellular carcinoma (HCC) is highly attributed to hepatic cancer stem cells (HCSCs). HCSCs are under microenvironment control. This work aimed to assess the systemic effect of ellagic acid (EA) on the HCC microenvironment to decline HCSCs. Fifty Wistar rats were divided into six groups: negative control (CON), groups 2 and 3 for solvents (DMSO), and (OVO). Group 4 was administered EA only. The (HCC-M) group, utilized as an HCC model, administered CCL4 (0.5 mL/kg in OVO) 1:1v/v, i.p) for 16 weeks. HCC-M rats were treated orally with EA (EA + HCC) 50 mg/kg bw for five weeks. Biochemical, morphological, histopathological, and immunohistochemical studies, and gene analysis using qRT-PCR were applied. Results revealed elevated liver injury biomarkers ALT, AST, ALP, and tumor biomarkers AFP and GGT, and marked nodularity of livers of HCC-M. EA effectively reduced the biomarkers and restored the altered structure of the livers. At the mRNA level, EA downregulated the expression of TGF-α, TGF-β, and VEGF, and restored p53 expression. This induced an increase in apoptotic cells immunostained with caspase3 and decreased the CD44 immunostained HCSCs. EA could modulate the tumor microenvironment in the HCC rat model and ultimately target the HCSCs.
肝细胞癌（HCC）的治疗抵抗与复发在很大程度上归因于肝癌干细胞（HCSCs）的存在，而HCSCs受肿瘤微环境调控。本研究旨在评估鞣花酸（EA）对HCC微环境的系统性作用及其对HCSCs的抑制效果。实验将50只Wistar大鼠分为六组：阴性对照组（CON）、溶剂对照组（DMSO组与OVO组）、单独EA给药组（EA组）。HCC模型组（HCC-M）通过腹腔注射四氯化碳（CCL4，0.5 mL/kg，以OVO为溶剂按1:1体积比配制）持续16周建立模型。随后对HCC-M组大鼠以50 mg/kg体重的剂量口服EA干预五周（EA+HCC组）。研究采用生化、形态学、组织病理学、免疫组织化学检测及qRT-PCR基因分析等方法进行评估。结果显示，HCC-M组大鼠肝脏损伤标志物（ALT、AST、ALP）和肿瘤标志物（AFP、GGT）显著升高，肝脏呈现明显结节样改变。EA干预有效降低了这些生物标志物水平，并改善了肝脏结构异常。在mRNA水平上，EA下调了TGF-α、TGF-β和VEGF的表达，同时恢复了p53的表达。这进一步诱导了caspase3免疫染色阳性凋亡细胞数量的增加，并减少了CD44免疫染色阳性的HCSCs。研究表明，EA能够调节HCC大鼠模型的肿瘤微环境，并最终靶向作用于HCSCs。
肿瘤(癌症)患者之家