| Peer-Reviewed

The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis

Received: 3 June 2022     Accepted: 17 June 2022     Published: 27 June 2022
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Abstract

Tumor angiogenesis is the center of tumor growth and metastasis, and it increases the supply of nutrients and oxygen to tumors, thereby supporting tumor growth and progression. Vascular endothelial growth factor (VEGF) is a stimulator of angiogenesis and also plays a key role in the process of angiogenesis. Overexpression of VEGF is associated with tumor angiogenesis, promotion of tumor growth and reduced survival rate of patients. Notch signaling is a key pathway that regulates the response to angiogenesis stimulation during embryonic vascular development and postnatal angiogenesis, and is involved in multiple steps of angiogenesis. Dll4 is the only Notch ligand mainly expressed in endothelial cells, which can propagate by activating Notch signal and regulate tumor angiogenesis. Notch signaling pathway and VEGF pathway have both independent and synergistic effects, and Notch is necessary for VEGF-mediated vascular remodeling. The pathways cross each other and jointly regulate tumor angiogenesis. This review reviews the relationship between dLL4-notch-VEGFR2 signaling pathway composition, transduction and regulation and tumor angiogenesis. Combined blocking of DLL4-notch-VEGFR2 signaling pathway can significantly reduce vascular perfusion, resulting in vascular degeneration and reduced tumor survival. It can destroy the vascular system and survival ability of the primary tumor more than blocking alone, thus providing a new idea for the treatment of tumor, which is of great significance for the future anti-angiogenesis therapy.

Published in Cancer Research Journal (Volume 10, Issue 2)
DOI 10.11648/j.crj.20221002.15
Page(s) 46-50
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2022. Published by Science Publishing Group

Keywords

DLL4, Notch, VEGF, Angiogenesis

References
[1] Parmar, D; Apte, M; Angiopoietin inhibitors: A review on targeting tumor angiogenesis. [J]. Eur J Pharmacol. 2021, 899: 174021.
[2] Zhao, Y; Chen, S; Gou, WF; et al. The role of EMMPRIN expression in ovarian epithelial carcinomas. [J]. Cell Cycle. 2013, 12 (17): 2899-913.
[3] Bridges, E; Oon, CE; Harris, A; Notch regulation of tumor angiogenesis. [J]. Future Oncol. 2011, 7 (4): 569-88.
[4] Briot, A; Iruela-Arispe, ML; Blockade of specific NOTCH ligands: a new promising approach in cancer therapy. [J]. Cancer Discov. 2015, 5 (2): 112-4.
[5] Jenkins, DW; Ross, S; Veldman-Jones, M; et al. MEDI0639: a novel therapeutic antibody targeting Dll4 modulates endothelial cell function and angiogenesis in vivo. [J]. Mol Cancer Ther. 2012, 11 (8): 1650-60.
[6] Zhu, G; Lin, Y; Ge, T; et al. A novel inhibitory peptide of Dll4-Notch1 signaling and its proangiogenic functions. [J]. Br J Pharmacol. 2021.
[7] Tang, Q; Jin, H; Tong, M; et al. Inhibition of Dll4/Notch1 pathway promotes angiogenesis of Masquelet's induced membrane in rats. [J]. Exp Mol Med. 2018, 50 (4): 1-15.
[8] Kangsamaksin, T; Murtomaki, A; Kofler, NM; et al. NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth. [J]. Cancer Discov. 2015, 5 (2): 182-97.
[9] Pries AR, Hopfner M, le Noble F, Dewhirst MW, Secomb TW: The shunt problem: control of functional shunting in normal and tumour vasculature. Nat Rev Cancer 2010, 10: 587-593.
[10] Zhao, D; Xue, C; Lin, S; et al. Notch Signaling Pathway Regulates Angiogenesis via Endothelial Cell in 3D Co-Culture Model. [J]. J Cell Physiol. 2017, 232 (6): 1548-1558.
[11] Kangsamaksin, T; Tattersall, IW; Kitajewski, J; Notch functions in developmental and tumour angiogenesis by diverse mechanisms. [J]. Biochem Soc Trans. 2014, 42 (6): 1563-8.
[12] Toro RD, Prahst C, Mathivet T, Siegfried G, Kaminker JS, Larrivee B, Breant C, et al. Identification and functional analysis of endothelial tip cell-enriched genes. Blood 2010, 116: 4025–4033.
[13] Pitulescu, ME; Schmidt, I; Giaimo, BD; et al. Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. [J]. Nat Cell Biol. 2017, 19 (8): 915-927.
[14] Pratt, EB; Wentzell, JS; Maxson, JE; et al. The cell giveth and the cell taketh away: an overview of Notch pathway activation by endocytic trafficking of ligands and receptors. [J]. Acta Histochem. 2011, 113 (3): 248-55.
[15] Park, JK; Lee, TW; Do, EK; et al. Role of Notch1 in the arterial specification and angiogenic potential of mouse embryonic stem cell-derived endothelial cells. [J]. Stem Cell Res Ther. 2018, 9 (1): 197.
[16] Robciuc, MR; Kivelä, R; Williams, IM; et al. VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications. [J]. Cell Metab. 2016, 23 (4): 712-24.
[17] Wang, H; Huang, X; Zhang, J; et al. The expression of VEGF and Dll4/Notch pathway molecules in ovarian cancer. [J]. Clin Chim Acta. 2014, 436: 243-8.
[18] Yu, S; Sun, J; Zhang, J; et al. Aberrant expression and association of VEGF and Dll4/Notch pathway molecules under hypoxia in patients with lung cancer. [J]. Histol Histopathol. 2013, 28 (2): 277-84.
[19] Wang, Y; Singh, AR; Zhao, Y; et al. TRIM28 regulates sprouting angiogenesis through VEGFR-DLL4-Notch signaling circuit. [J]. FASEB J. 2020, 34 (11): 14710-14724.
[20] Pietras, A; von Stedingk, K; Lindgren, D; et al. JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation. [J]. Mol Cancer Res.: 626-36.
[21] Yan, M; Therapeutic promise and challenges of targeting DLL4/NOTCH1. [J]. Vasc Cell. 2011, 3: 17.
[22] Trindade, A; Djokovic, D; Gigante, J; et al. Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo. [J]. BMC Cancer. 2017, 17 (1): 189.
[23] Yang, L; Wang, X; Sun, J; et al. Neuritin promotes angiogenesis through inhibition of DLL4/Notch signaling pathway. [J]. Acta Biochim Biophys Sin (Shanghai). 2021, 53 (6): 663-672.
[24] Guo, D; Li, C; Teng, Q; et al. Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma. [J]. Neoplasma. 2013, 60 (1): 33-40.
[25] Hernandez, SL; Banerjee, D; Garcia, A; et al. Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis. [J]. Vasc Cell. 2013, 5 (1): 17.
[26] Sun, L; Yang, Q; Wang, P; et al. The influence of YS-1 on the Dll4-Notch1 signaling pathway. [J]. Acta Biochim Biophys Sin (Shanghai). 2014, 46 (1): 56-64.
[27] Funahashi, Y; Shawber, CJ; Sharma, A; et al. Notch modulates VEGF action in endothelial cells by inducing Matrix Metalloprotease activity. [J]. Vasc Cell. 2011, 3 (1): 2.
[28] Fischer, M; Yen, WC; Kapoun, AM; et al. Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. [J]. Cancer Res. 2011, 71 (5): 1520-5.
[29] Marchetto, NM; Begum, S; Wu, T; et al. Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy. [J]. Int J Mol Sci. 2020, 21 (18).
[30] Yuan, C; Wu, C; Xue, R; et al. Suppression of human colon tumor by EERAC through regulating Notch/DLL4/Hes pathway inhibiting angiogenesis in vivo. [J]. J Cancer. 2021, 12 (19): 5914-5922.
Cite This Article
  • APA Style

    Jie Zhou, Xinxin Duan, Ting Xiong, Aixia Sui. (2022). The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis. Cancer Research Journal, 10(2), 46-50. https://doi.org/10.11648/j.crj.20221002.15

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    ACS Style

    Jie Zhou; Xinxin Duan; Ting Xiong; Aixia Sui. The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis. Cancer Res. J. 2022, 10(2), 46-50. doi: 10.11648/j.crj.20221002.15

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    AMA Style

    Jie Zhou, Xinxin Duan, Ting Xiong, Aixia Sui. The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis. Cancer Res J. 2022;10(2):46-50. doi: 10.11648/j.crj.20221002.15

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  • @article{10.11648/j.crj.20221002.15,
      author = {Jie Zhou and Xinxin Duan and Ting Xiong and Aixia Sui},
      title = {The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis},
      journal = {Cancer Research Journal},
      volume = {10},
      number = {2},
      pages = {46-50},
      doi = {10.11648/j.crj.20221002.15},
      url = {https://doi.org/10.11648/j.crj.20221002.15},
      eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.crj.20221002.15},
      abstract = {Tumor angiogenesis is the center of tumor growth and metastasis, and it increases the supply of nutrients and oxygen to tumors, thereby supporting tumor growth and progression. Vascular endothelial growth factor (VEGF) is a stimulator of angiogenesis and also plays a key role in the process of angiogenesis. Overexpression of VEGF is associated with tumor angiogenesis, promotion of tumor growth and reduced survival rate of patients. Notch signaling is a key pathway that regulates the response to angiogenesis stimulation during embryonic vascular development and postnatal angiogenesis, and is involved in multiple steps of angiogenesis. Dll4 is the only Notch ligand mainly expressed in endothelial cells, which can propagate by activating Notch signal and regulate tumor angiogenesis. Notch signaling pathway and VEGF pathway have both independent and synergistic effects, and Notch is necessary for VEGF-mediated vascular remodeling. The pathways cross each other and jointly regulate tumor angiogenesis. This review reviews the relationship between dLL4-notch-VEGFR2 signaling pathway composition, transduction and regulation and tumor angiogenesis. Combined blocking of DLL4-notch-VEGFR2 signaling pathway can significantly reduce vascular perfusion, resulting in vascular degeneration and reduced tumor survival. It can destroy the vascular system and survival ability of the primary tumor more than blocking alone, thus providing a new idea for the treatment of tumor, which is of great significance for the future anti-angiogenesis therapy.},
     year = {2022}
    }
    

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  • TY  - JOUR
    T1  - The Role of DLL4-Notch-VEGFR2 Signaling Pathway in Tumor Angiogenesis
    AU  - Jie Zhou
    AU  - Xinxin Duan
    AU  - Ting Xiong
    AU  - Aixia Sui
    Y1  - 2022/06/27
    PY  - 2022
    N1  - https://doi.org/10.11648/j.crj.20221002.15
    DO  - 10.11648/j.crj.20221002.15
    T2  - Cancer Research Journal
    JF  - Cancer Research Journal
    JO  - Cancer Research Journal
    SP  - 46
    EP  - 50
    PB  - Science Publishing Group
    SN  - 2330-8214
    UR  - https://doi.org/10.11648/j.crj.20221002.15
    AB  - Tumor angiogenesis is the center of tumor growth and metastasis, and it increases the supply of nutrients and oxygen to tumors, thereby supporting tumor growth and progression. Vascular endothelial growth factor (VEGF) is a stimulator of angiogenesis and also plays a key role in the process of angiogenesis. Overexpression of VEGF is associated with tumor angiogenesis, promotion of tumor growth and reduced survival rate of patients. Notch signaling is a key pathway that regulates the response to angiogenesis stimulation during embryonic vascular development and postnatal angiogenesis, and is involved in multiple steps of angiogenesis. Dll4 is the only Notch ligand mainly expressed in endothelial cells, which can propagate by activating Notch signal and regulate tumor angiogenesis. Notch signaling pathway and VEGF pathway have both independent and synergistic effects, and Notch is necessary for VEGF-mediated vascular remodeling. The pathways cross each other and jointly regulate tumor angiogenesis. This review reviews the relationship between dLL4-notch-VEGFR2 signaling pathway composition, transduction and regulation and tumor angiogenesis. Combined blocking of DLL4-notch-VEGFR2 signaling pathway can significantly reduce vascular perfusion, resulting in vascular degeneration and reduced tumor survival. It can destroy the vascular system and survival ability of the primary tumor more than blocking alone, thus providing a new idea for the treatment of tumor, which is of great significance for the future anti-angiogenesis therapy.
    VL  - 10
    IS  - 2
    ER  - 

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Author Information
  • Graduate School, North China University of Science and Technology, Tangshan, China

  • Graduate School, North China University of Science and Technology, Tangshan, China

  • Graduate School, North China University of Science and Technology, Tangshan, China

  • Department of Sixth Oncology, Hebei General Hospital, Shijiazhuang, China

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