Patel Shovik S, Sandur Amitha, El-Kebir Mohammed, Gaba Ron C, Schook Lawrence B, Schachtschneider Kyle M
Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States.
Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
Front Genet. 2021 Apr 29;12:657330. doi: 10.3389/fgene.2021.657330. eCollection 2021.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model-a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of and driver mutations-has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors ( = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling , improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.
肝细胞癌（HCC）是全球癌症相关死亡的第二大主要原因，是最常见的肝癌形式。随着HCC发病率和死亡率持续上升，越来越需要改进转化动物模型，以弥合HCC基础研究与临床实践之间的差距，从而改善针对这种致命疾病的早期检测和治疗策略。最近，Oncopig癌症模型——一种通过Cre重组酶诱导表达 和 驱动突变来模拟人类癌症的新型转基因猪模型——已被验证为人类HCC的大型动物转化模型。由于猪和人类在大小、解剖结构、生理学、免疫学、遗传学和表观遗传学方面相似，Oncopig有潜力改善将新型诊断和治疗方法转化为临床实践的过程。最近的研究表明，肿瘤细胞在将其周围微环境塑造成一个更具增殖性、侵袭性和转移性的微环境方面具有重要作用；然而，关于微环境信号对HCC肿瘤生物学以及HCC肿瘤与其肿瘤微环境（TME）之间差异基因表达的影响，人们知之甚少。在本研究中，对通过将Oncopig HCC细胞皮下注射到严重联合免疫缺陷（SCID）小鼠体内产生的Oncopig HCC异种移植肿瘤（ = 3）进行了转录谱分析。为了区分肿瘤和周围肿瘤微环境中的基因表达，使用Xenome对源自猪（HCC肿瘤）和小鼠（微环境）细胞的RNA-seq读数进行了生物信息学分离。主成分分析（PCA）表明，基于直系同源基因的表达，样本按组聚类。提取对每个主成分有贡献的基因并进行功能分析，以确定HCC细胞与微环境之间通路信号的改变。观察到与肝纤维化沉积、免疫反应和新生血管生成相关的基因表达发生了变化。本研究结果为HCC与微环境信号之间的相互作用提供了见解，增进了我们对HCC肿瘤细胞、周围肿瘤微环境之间相互作用以及对HCC发生发展影响的理解。
