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The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression.

ABSTRACT: Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.

SUBMITTER: Ciesielski O

PROVIDER: S-EPMC7177242 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression.

Ciesielski Oskar O Biesiekierska Marta M Panthu Baptiste B Vialichka Varvara V Pirola Luciano L Balcerczyk Aneta A

International journal of molecular sciences 20200409 7

Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, prol ...[more]

PMID: 32283668

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Project description:Multicellular tumor spheroids (MCTS) are valuable in vitro tumor models frequently used to evaluate the penetration and efficacy of therapeutics. In this study, we evaluated potential differences in epigenetic markers, i.e., histone post-translational modifications (PTMs), in the layers of the HCT116 colon carcinoma MCTS. Cells were grown in agarose-coated 96 well plates, forming reproducible 1-mm-diameter MCTS. The MCTS were fractionated into three radially concentric portions, generating samples containing cells from the core, the mid and the external layers. Using mass spectrometry (MS)-based proteomics and EpiProfile, we quantified hundreds of histone peptides in different modified forms; by combining the results of all experiments, we quantified the abundance of 258 differently modified peptides, finding significant differences in their relative abundance across layers. Among these differences, we detected higher amounts of the repressive mark H3K27me3 in the external layers, compared to the core. We then evaluated the epigenetic response of MCTS following UNC1999 treatment, a drug targeting the enzymes that catalyze H3K27me3, namely, the polycomb repressive complex 2 (PRC2) subunits enhancer of zeste 1 (EZH1) and enhancer of zeste 2 (EZH2). UNC1999 treatment resulted in significant differences in MCTS diameter under drug treatment of varying duration. Using matrix-assisted laser desorption/ionization (MALDI) imaging, we determined that the drug penetrates the entire MCTS. Proteomic analysis revealed a decrease in abundance of H3K27me3, compared to the untreated sample, as expected. Interestingly, we observed a comparable growth curve for MCTS under constant drug treatment over 13 days with those treated for only 4 days at the beginning of their growth. We thus demonstrate that MS-based proteomics can define significant differences in histone PTM patterns in submillimetric layers of three-dimensional (3D) cultures. Moreover, we show that our model is suitable for monitoring drug localization and regulation of histone PTMs after drug treatment.

Dataset Information

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression.

Publications

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression.

Similar Datasets

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