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.Int. J. Mol. Sci. 2020, 21, 2606 2 of 22 organ" spread over an area of approximately 7 m 2 that controls: (i) the flow of blood, (ii) organism nutrition by the passage of metabolites and gases exchange, (iii) immunity by circulating immune cells and antibodies, as well as (iv) trafficking of leukocytes [2][3][4]. Moreover, endothelial cells are involved in several physiological processes including (v) angiogenesis, (vi) blood coagulation and fibrinolysis, (vii) vasomotor and blood pressure regulation, and (viii) inflammatory reactions, which are conditioned by a multitude of synthesized and released hormonal and chemical mediators, including vascular endothelial growth factor (VEGF), nitric oxide (NO • ), or prostaglandin E2 [5][6][7].Dysfunction of the endothelium results in a number of disorders. In tumors, endothelial cells due to chronic stimulation by growth factors and hypoxia, change their phenotype into tumor endothelial cells (TECs), which results in abnormalities in tumor blood vessel morphology. TECs are fragile and leaky as compared to normal vessels, that in consequence alters blood flow. These abnormalities in the tumor endothelium contribute to tumor growth and metastasis [8,9]. Thus, a detailed under...

Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

“…For example, EZH2 a specific histone methyl transferase is a driver of sunitinib resistance in kidney cancers (Adelaiye-Ogala et al, 2017). In addition to tumor cells, tumor endothelial cells undergo epigenetic modifications crucial for adaptation to the antiangiogenic therapies (Ciesielski et al, 2020).…”

Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

“…During the angiogenesis, cell proliferation, differentiation and migration, cell-ECM adhesions, intercellular signaling cascades, and tumor cell-stromal cell interactions all participate and are coordinated with each other. The epigenetic regulation of angiogenesis, and proangiogenic factors-associated angiogenic switch of ECs were extensively reviewed in Ciesielski et al (2020) and Tan et al (2020) . In this mini review, we only summarized the specific angiogenesis related to the resistance of AATs.…”

Activated melanoma vessels: A sticky point for successful immunotherapy

“…[20] Therefore, the endothelial cells within tumor vasculature have been pinpointed as a target for investigations and therapeutic interventions. [21] Initial studies in the 1990s aiming at defining adhesion molecule expression on tumor vasculature were undertaken to develop melanoma vaccination protocols or antigen unspecific immunotherapy concepts (interferon-α, interleukin-2, isolated limb perfusion with TNF). [22][23][24] Recent antigen non-specific approaches like CTLA-4 and PD-1 inhibition still require homing prerequisites, like adhesion molecule expression on tumor vasculature and chemokine gradients inside tumor tissue for effective immune infiltration.…”

“…[ 20 ] Therefore, the endothelial cells within tumor vasculature have been pinpointed as a target for investigations and therapeutic interventions. [ 21 ]…”