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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 30219

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Special Issue Editors

Prof. Dr. Kyoko Hida

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Guest Editor

Vascular Biology and Molecular Pathology, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-8586, Japan
Interests: tumor angiogenesis; antiangiogenic therapy; tumor microenvironment; tumor endothelial cell

Prof. Dr. Nobuyuki Takakura

E-Mail Website
Guest Editor

Research Institute for Microbial Diseases, Osaka University, Suita, Japan
Interests: angiogenesis; vasculogenesis; endothelium; tumor; stem cell; development

Special Issue Information

Dear Colleagues,

Tumor blood vessels supply the tumor with oxygen and nutrients and provide a gateway for tumor metastasis; thus, tumor progression depends on angiogenesis. Since the approval of the first antiangiogenic drug, bevacizumab, tumor endothelial cells (TECs) have been considered “the second most important target for cancer therapy”. Antiangiogenic drugs have shown their benefit when used in combination with chemotherapeutic drugs. However, it has been reported that these drugs have several issues that need to be overcome, such as side effects and drug resistance. Recent studies have elucidated that TECs differ from normal endothelial cells (NECs) both morphologically and physiologically, contrary to previous presumptions. Additionally, it has been reported that TECs are not homogeneous and constitute a heterogeneous population. To develop novel cancer therapy, it is important to study TECs. This Special Issue focuses on tumor endothelial cell biology and discussing the consequence of their altered phenotypes.

Prof. Dr. Kyoko Hida
Prof. Dr. Nobuyuki Takakura
Guest Editor

Manuscript Submission Information

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Keywords

Tumor angiogenesis
Antiangiogenic therapy
Tumor microenvironment
Tumor endothelial cell

Published Papers (7 papers)

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Research

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10 pages, 1896 KiB

Open AccessArticle

Glioblastoma Cells Do Not Affect Axitinib-Dependent Senescence of HUVECs in a Transwell Coculture Model

by Matilde Merolle, Maria Patrizia Mongiardi, Maurizia Piras, Andrea Levi and Maria Laura Falchetti

Int. J. Mol. Sci. 2020, 21(4), 1490; https://doi.org/10.3390/ijms21041490 - 21 Feb 2020

Cited by 6 | Viewed by 3426

Abstract

Axitinib is an orally available inhibitor of tyrosine kinases, with high specificity for vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is approved for the treatment of advanced renal cell carcinoma and is in phase II clinical trials for recurrent glioblastoma (GBM). GBM is a brain tumor peculiar in its ability to induce neoangiogenesis. Since both GBM tumor cells and endothelial cells of tumor vasculature express VEGFRs, Axitinib exerts its inhibitory action on both tumor and endothelial cells. We and others previously demonstrated that Axitinib triggers cellular senescence. In particular, Axitinib-dependent senescence of HUVECs (human umbilical vein endothelial cells) is accompanied by intracellular reactive oxygen species(ROS) increase and early ataxia telangiectasia mutated(ATM) activation. Here we wondered if the presence of glioblastoma tumor cells could affect the HUVEC senescence upon Axitinib exposure. To address this issue, we cocultured HUVECs together with GBM tumor cells in transwell plates. HUVEC senescence did not result in being affected by GBM cells, neither in terms of β galactosidase activity nor of proliferation index or ATM phosphorylation. Conversely, Axitinib modulation of HUVEC gene expression was altered by cocultured GBM cells. These data demonstrate that the GBM secretome modifies HUVECs’ transcriptomic profile upon Axitinib exposure, but does not prevent drug-induced senescence. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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15 pages, 1956 KiB

Open AccessArticle

Development of Immortalized Human Tumor Endothelial Cells from Renal Cancer

by Nako Maishi, Hiroshi Kikuchi, Masumi Sato, Hiroko Nagao-Kitamoto, Dorcas A. Annan, Shogo Baba, Takayuki Hojo, Misa Yanagiya, Yusuke Ohba, Genichiro Ishii, Kenkichi Masutomi, Nobuo Shinohara, Yasuhiro Hida and Kyoko Hida

Int. J. Mol. Sci. 2019, 20(18), 4595; https://doi.org/10.3390/ijms20184595 - 17 Sep 2019

Cited by 9 | Viewed by 4913

Abstract

Tumor angiogenesis research and antiangiogenic drug development make use of cultured endothelial cells (ECs) including the human microvascular ECs among others. However, it has been reported that tumor ECs (TECs) are different from normal ECs (NECs). To functionally validate antiangiogenic drugs, cultured TECs are indispensable tools, but are not commercially available. Primary human TECs are available only in small quantities from surgical specimens and have a short life span in vitro due to their cellular senescence. We established immortalized human TECs (h-imTECs) and their normal counterparts (h-imNECs) by infection with lentivirus producing simian virus 40 large T antigen and human telomerase reverse transcriptase to overcome the replication barriers. These ECs exhibited an extended life span and retained their characteristic endothelial morphology, expression of endothelial marker, and ability of tube formation. Furthermore, h-imTECs showed their specific characteristics as TECs, such as increased proliferation and upregulation of TEC markers. Treatment with bevacizumab, an antiangiogenic drug, dramatically decreased h-imTEC survival, whereas the same treatment failed to alter immortalized NEC survival. Hence, these h-imTECs could be a valuable tool for drug screening to develop novel therapeutic agents specific to TECs or functional biological assays in tumor angiogenesis research. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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Review

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33 pages, 1584 KiB

Open AccessReview

Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

by Eva Andreuzzi, Alessandra Capuano, Evelina Poletto, Eliana Pivetta, Albina Fejza, Andrea Favero, Roberto Doliana, Renato Cannizzaro, Paola Spessotto and Maurizio Mongiat

Int. J. Mol. Sci. 2020, 21(10), 3686; https://doi.org/10.3390/ijms21103686 - 23 May 2020

Cited by 20 | Viewed by 4740

Abstract

Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients’ outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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21 pages, 3014 KiB

Open AccessReview

Tumor Endothelial Cell—A Biological Tool for Translational Cancer Research

by Dorcas Akuba-Muhyia Annan, Hiroshi Kikuchi, Nako Maishi, Yasuhiro Hida and Kyoko Hida

Int. J. Mol. Sci. 2020, 21(9), 3238; https://doi.org/10.3390/ijms21093238 - 03 May 2020

Cited by 20 | Viewed by 3744

Abstract

Going from bench to bedside is a simplified description of translational research, with the ultimate goal being to improve the health status of mankind. Tumor endothelial cells (TECs) perform angiogenesis to support the growth, establishment, and dissemination of tumors to distant organs. TECs have various features that distinguish them from normal endothelial cells, which include alterations in gene expression patterns, higher angiogenic and metabolic activities, and drug resistance tendencies. The special characteristics of TECs enhance the vulnerability of tumor blood vessels toward antiangiogenic therapeutic strategies. Therefore, apart from being a viable therapeutic target, TECs would act as a better mediator between the bench (i.e., angiogenesis research) and the bedside (i.e., clinical application of drugs discovered through research). Exploitation of TEC characteristics could reveal unidentified strategies of enhancing and monitoring antiangiogenic therapy in the treatment of cancer, which are discussed in this review. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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22 pages, 1736 KiB

Open AccessReview

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

by Oskar Ciesielski, Marta Biesiekierska, Baptiste Panthu, Varvara Vialichka, Luciano Pirola and Aneta Balcerczyk

Int. J. Mol. Sci. 2020, 21(7), 2606; https://doi.org/10.3390/ijms21072606 - 09 Apr 2020

Cited by 26 | Viewed by 4062

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. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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16 pages, 1092 KiB

Open AccessReview

Alternative Strategies to Inhibit Tumor Vascularization

by Alessia Brossa, Lola Buono, Sofia Fallo, Alessandra Fiorio Pla, Luca Munaron and Benedetta Bussolati

Int. J. Mol. Sci. 2019, 20(24), 6180; https://doi.org/10.3390/ijms20246180 - 07 Dec 2019

Cited by 11 | Viewed by 3268

Abstract

Endothelial cells present in tumors show different origin, phenotype, and genotype with respect to the normal counterpart. Various mechanisms of intra-tumor vasculogenesis sustain the complexity of tumor vasculature, which can be further modified by signals deriving from the tumor microenvironment. As a result, resistance to anti-VEGF therapy and activation of compensatory pathways remain a challenge in the treatment of cancer patients, revealing the need to explore alternative strategies to the classical anti-angiogenic drugs. In this review, we will describe some alternative strategies to inhibit tumor vascularization, including targeting of antigens and signaling pathways overexpressed by tumor endothelial cells, the development of endothelial vaccinations, and the use of extracellular vesicles. In addition, anti-angiogenic drugs with normalizing effects on tumor vessels will be discussed. Finally, we will present the concept of endothelial demesenchymalization as an alternative approach to restore normal endothelial cell phenotype. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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15 pages, 287 KiB

Open AccessReview

Targeting Tumor Endothelial Cells with Nanoparticles

by Yu Sakurai, Hidetaka Akita and Hideyoshi Harashima

Int. J. Mol. Sci. 2019, 20(23), 5819; https://doi.org/10.3390/ijms20235819 - 20 Nov 2019

Cited by 31 | Viewed by 5302

Abstract

Because angiogenesis is a major contributor to cancer progression and metastasis, it is an attractive target for cancer therapy. Although a diverse number of small compounds for anti-angiogenic therapy have been developed, severe adverse effects commonly occur, since small compounds can affect not only tumor endothelial cells (TECs), but also normal endothelial cells. This low selectivity for TECs has motivated researchers to develop alternate types of drug delivery systems (DDSs). In this review, we summarize the current state of knowledge concerning the delivery of nano DDSs to TECs. Their payloads range from small compounds to nucleic acids. Perspectives regarding new therapeutic targets are also mentioned. Full article

(This article belongs to the Special Issue Advanced Research on Tumor Endothelial Cells)

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