Bouzas Muñoz Adrián, Giménez-Bastida Juan Antonio, Tejedor Aurora García, Haros Claudia Monika, Gómez de Cedrón Marta, Ramírez de Molina Ana, Laparra Llopis José Moisés
Molecular Immunonutrition Group, Madrid Institute for Advanced Studies in Food (IMDEA Food), Ctra Cantoblanco 8, 28049 Madrid, Spain.
Molecular Oncology Group, Madrid Institute for Advanced Studies in Food (IMDEA Food), 28049 Madrid, Spain.
Biomedicines. 2021 Nov 6;9(11):1633. doi: 10.3390/biomedicines9111633.
Innate immunity in the tumor microenvironment plays a pivotal role in hepatocarcinoma (HCC) progression. Plant seeds provide serine-type protease inhibitors (SETIs), which can have a significant influence on liver inflammation and macrophage function. To elucidate the influence of SETIs to counter pro-tumorigenic conditions, at the early stages of HCC development, it was used as an established model of diethylnitrosamine/thioacetamide-injured liver fed with a standard diet (STD) or high-fat diet (42%) (HFD). The administration of SETIs improved survival and ameliorated tumor burden via modulation of monocyte-derived macrophages as key effectors involved in diet-induced HCC development. RT-qPCR analyses of hepatic tissue evidenced a diet-independent downregulatory effect of SETIs on the transcripts of CD36, FASN, ALOX15, and SREBP1c; however, animals fed with an STD showed opposing effects for PPAR and NRLP3 levels. These effects were accompanied by a decreased production of IL-6 and IL-17 but increased that of TNF in animals receiving SETIs. Moreover, only animals fed an HFD displayed increased concentrations of the stem cell factor. Overall, SETIs administration decreased the hepatic contents of lysophosphatydilcholine, phosphatidylinositol, phosphatidylcholine, and phosphatidyl ethanolamine. Notably, animals that received SETIs exhibited increased hepatic proportions of CD68CX3CR1CD74 cells and at a higher rate in those animals fed an HFD. Altogether, the data evidence that oral administration of SETIs modulates the tumor microenvironment, improving hepatic innate immune response(s) and favoring a better antitumoral environment. It represents a path forward in developing coadjutant strategies to pharmacological therapies, with either a preventive or therapeutic character, to counter physiopathological conditions at early stages of HCC development.
肿瘤微环境中的固有免疫在肝癌（HCC）进展中起关键作用。植物种子提供丝氨酸型蛋白酶抑制剂（SETIs），其可对肝脏炎症和巨噬细胞功能产生重大影响。为了阐明SETIs对对抗促肿瘤条件的影响，在HCC发展的早期阶段，将其用作喂食标准饮食（STD）或高脂饮食（42%）（HFD）的二乙基亚硝胺/硫代乙酰胺损伤肝脏的既定模型。SETIs的给药通过调节单核细胞衍生的巨噬细胞改善了存活率并减轻了肿瘤负担，单核细胞衍生的巨噬细胞是饮食诱导的HCC发展中的关键效应器。肝组织的RT-qPCR分析证明SETIs对CD36、FASN、ALOX15和SREBP1c的转录本具有饮食无关的下调作用；然而，喂食STD的动物对PPAR和NRLP3水平显示出相反的作用。这些作用伴随着接受SETIs的动物中IL-6和IL-17的产生减少，但TNF的产生增加。此外，仅喂食HFD的动物显示干细胞因子浓度增加。总体而言，SETIs给药降低了溶血磷脂酰胆碱、磷脂酰肌醇、磷脂酰胆碱和磷脂酰乙醇胺的肝脏含量。值得注意的是，接受SETIs的动物肝脏中CD68CX3CR1CD74细胞的比例增加，在喂食HFD的动物中比例更高。总之，数据证明口服SETIs可调节肿瘤微环境，改善肝脏固有免疫反应并有利于更好的抗肿瘤环境。它代表了在开发具有预防或治疗性质的辅助策略以对抗HCC发展早期的生理病理状况方面的一条前进道路，这些策略可与药物治疗相结合。
