Systematic Analysis of the Transcriptome Profiles and Co-Expression Networks of Tumour Endothelial Cells Identifies Several Tumour-Associated Modules and Potential Therapeutic Targets in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related death, with tumour associated liver endothelial cells being thought to be major drivers in HCC progression. This study aims to compare the gene expression profiles of tumour endothelial cells from the liver with endothelial cells from non-tumour liver tissue, to identify perturbed biologic functions, co-expression modules, and potentially drugable hub genes that could give rise to novel therapeutic targets and strategies. Gene Set Variation Analysis (GSVA) showed that cell growth-related pathways were upregulated, whereas apoptosis induction, immune and inflammatory-related pathways were downregulated in tumour endothelial cells. Weighted Gene Co-expression Network Analysis (WGCNA) identified several modules strongly associated to tumour endothelial cells or angiogenic activated endothelial cells with high endoglin (ENG) expression. In tumour cells, upregulated modules were associated with cell growth, cell proliferation, and DNA-replication, whereas downregulated modules were involved in immune functions, particularly complement activation. In ENG+ cells, upregulated modules were associated with cell adhesion and endothelial functions. One downregulated module was associated with immune system-related functions. Querying the STRING database revealed known functional-interaction networks underlying the modules. Several possible hub genes were identified, of which some (for example FEN1, BIRC5, NEK2, CDKN3, and TTK) are potentially druggable as determined by querying the Drug Gene Interaction database. In summary, our study provides a detailed picture of the transcriptomic differences between tumour and non-tumour endothelium in the liver on a co-expression network level, indicates several potential therapeutic targets and presents an analysis workflow that can be easily adapted to other projects.

Tumour endothelial cells for translational research and therapeutics

“…It is well documented that the difference in gene expression between TECs and NECs 3,17,54 may be due to the different origins and high mutagenicity of TECs. However, only a few studies have shown that the changes of biological functions of endothelial cells are caused by overexpression or low expression of differential genes in TECs.…”

“…It may be that endothelial cells (ECs) are embedded in the vascular wall, which is difficult to separate, and the number of cells is small, so it is necessary to evaluate the gene expression profile of fewer cells 17 . Genome variation analysis shows the gene expression profile of TECs, providing a framework for gene analysis of TECs in the future 54 . With the application of scRNA‐seq technology, the transcriptome of TECs has gradually been elucidated 61 .…”

“…17 Genome variation analysis shows the gene expression profile of TECs, providing a framework for gene analysis of TECs in the future. 54 With the application of scRNA-seq technology, the transcriptome of TECs has gradually been elucidated. 61 Zhao et al tried to divide TECs into three subpopulations, including tip like, transition and stack like cells.…”

Mesothelioma-associated fibroblasts enhance proliferation and migration of pleural mesothelioma cells via c-Met/PI3K and WNT signaling but do not protect against cisplatin

“…Gene expression data of Meso-CAFs was compared to CAF-3 and to data of 31 PM cell lines available from a previous publication [10]. Analysis and comparison of expression data was conducted in R [13], and differentially expressed genes between cell types (Meso-CAF, CAF-3, PM) were determined using "limma" package [14] as previously described by Mohr et al [15]. Genes with multiple oligonucleotide probes on the array were summarized to the probe with maximal interquartile range using the package "gene lter" [16].…”

Special Issue: “New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors (STRATAGEM Special Issue, EU-COST CA17104)”

“…The European COST (Cooperation in Science and Technology) Action STRATAGEM “New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors” was initiated in April 2018, as a multidisciplinary open consortium studying the diagnostic, therapeutic and toxicological challenges associated with MDR tumors. Indeed, multiple tools must be used to overcome MDR, including molecular modelling [ 12 ], high-throughput bioinformatic analyses [ 9 , 13 ], biochemical and pharmacological assays together with advanced technological tools [ 14 ], rational design and synthesis of new synthetic or natural bioactive compounds [ 10 , 15 , 16 ] and preparation of formulations using nanocarriers to improve drug solubilization, selectivity and anti-cancer action [ 11 ].…”