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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Network-Based Analysis Reveals Gene Signature in Tip Cells and Stalk Cells

Author(s): Lingyun Xu and Chen Li*

Volume 22, Issue 8, 2022

Published on: 20 July, 2021

Page: [1571 - 1581] Pages: 11

DOI: 10.2174/1871520621666210720120218

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Abstract

Background: Angiogenesis occurs during various physiological or pathological processes such as wound healing and tumor growth. Differentiation of vascular endothelial cells into tip cells and stalk cells initiates the formation of new blood vessels. Tip cells and stalk cells are endothelial cells with different biological characteristics and functions.

Objective: The aim of this study was to determine the mechanisms of angiogenesis by exploring differences in gene expression of tip cells and stalk cells.

Methods: Raw data were retrieved from NCBI Gene Expression Omnibus (GSE19284). Data were reanalyzed using bioinformatics methods that employ robust statistical methods, including identification of differentially expressed genes (DEGs) between the stalk and tip cells, Weighted Gene Correlation Network Analysis (WGCNA), gene ontology and pathway enrichment analysis using DAVID tools, integration of Protein-Protein Interaction (PPI) networks and screening of hub genes. DEGs of stalk and tip cells were grouped as dataset A. Gene modules associated with differentiation of stalk and tip cells screened by WGCNA were named dataset B. Further, we retrieved existing markers of angiogenesis from previous experimental studies on tip and stalk cells which we called dataset C. Intersection of datasets A, B and C was used as a candidate gene. Subsequently, we verified the results applying Quantitative Polymerase Chain Reaction (Q-PCR) to our clinical specimen. In general, the Q‐PCR results coincide with the majority of the expression profile.

Results: We identified five candidate genes, including ESM1, CXCR4, JAG1, FLT1 and PTK2, and two pathways, including Rap1 signaling pathway and PI3K-Akt signaling pathway in vascular endothelial cells that differentiate into tip cells and stalk cells using bioinformatics analysis.

Conclusion: Bioinformatics approaches provide new avenues for basic research in different fields such as angiogenesis. The findings of this study provide new perspectives and a basis for the study of molecular mechanisms of vascular endothelial cell differentiation into stalk and tip cells. Genes and pathways identified in this study are potential biomarkers and therapeutic targets for angiogenesis in the tumor.

Keywords: Angiogenesis, tip cells and stalk cells, bioinformatics approach, differentially expressed genes, WGCNA, candidate genes, the therapeutic agent.

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[1]
Coultas, L.; Chawengsaksophak, K.; Rossant, J. Endothelial cells and VEGF in vascular development. Nature, 2005, 438(7070), 937-945.
[http://dx.doi.org/10.1038/nature04479] [PMID: 16355211]
[2]
Udan, R.S.; Culver, J.C.; Dickinson, M.E. Understanding vascular development. Wiley Interdiscip. Rev. Dev. Biol., 2013, 2(3), 327-346.
[http://dx.doi.org/10.1002/wdev.91] [PMID: 23799579]
[3]
Risau, W. Mechanisms of angiogenesis. Nature, 1997, 386(6626), 671-674.
[http://dx.doi.org/10.1038/386671a0] [PMID: 9109485]
[4]
Hellström, M.; Phng, L.K.; Hofmann, J.J. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature, 2007, 445(7129), 776-780.
[http://dx.doi.org/10.1038/nature05571] [PMID: 17259973]
[5]
Djonov, V.; Andres, A.C.; Ziemiecki, A. Vascular remodelling during the normal and malignant life cycle of the mammary gland. Microsc. Res. Tech., 2001, 52(2), 182-189.
[http://dx.doi.org/10.1002/1097-0029(20010115)52:2<182:AID-JEMT1004>3.0.CO;2-M] [PMID: 11169866]
[6]
Djonov, V; Schmid, M; Tschanz, SA; Burri, PH Intussusceptive angiogenesis: Its role in embryonic vascular network formation. circ res, 2000, 86(3), 286-92.
[http://dx.doi.org/10.1161/01.RES.86.3.286] [PMID: 10679480]
[7]
Potente, M.; Gerhardt, H.; Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell, 2011, 146(6), 873-887.
[http://dx.doi.org/10.1016/j.cell.2011.08.039] [PMID: 21925313]
[8]
Kurzyk, A. Angiogenesis - possibilities, problems and perspectives. Postepy Biochem., 2015, 61(1), 25-34.
[9]
Gerber, H.P.; Hillan, K.J.; Ryan, A.M. VEGF is required for growth and survival in neonatal mice. Development, 1999, 126(6), 1149-1159.
[10]
Dvorak, H.F. Vascular permeability factor/vascular endothelial growth factor. A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol., 2002, 20(21), 4368-4380.
[11]
Mac Gabhann, F.; Popel, A.S. Systems biology of vascular endothelial growth factors. Microcirculation, 2008, 15(8), 715-738.
[12]
Ruhrberg, C.; Gerhardt, H.; Golding, M. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev., 2002, 16(20), 2684-2698.
[13]
Jakobsson, L.; Franco, C.A.; Bentley, K. Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat. Cell Biol., 2010, 12(10), 943-953.
[http://dx.doi.org/10.1038/ncb2103] [PMID: 20871601]
[14]
Arima, S.; Nishiyama, K.; Ko, T. Angiogenic morphogenesis driven by dynamic and heterogeneous collective endothelial cell movement. Development, 2011, 138(21), 4763-4776.
[15]
Tammela, T.; Zarkada, G.; Nurmi, H. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat. Cell Biol., 2011, 13(10), 1202-1213.
[http://dx.doi.org/10.1038/ncb2331] [PMID: 21909098]
[16]
Vogelstein, B.; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A., Jr; Kinzler, K.W. Cancer genome landscapes. Science, 2013, 339(6127), 1546-1558.
[http://dx.doi.org/10.1126/science.1235122] [PMID: 23539594]
[17]
Nannini, M.; Pantaleo, M.A.; Maleddu, A.; Astolfi, A.; Formica, S.; Biasco, G. Gene expression profiling in colorectal cancer using microarray technologies: Results and perspectives. Cancer Treat. Rev., 2009, 35(3), 201-209.
[http://dx.doi.org/10.1016/j.ctrv.2008.10.006] [PMID: 19081199]
[18]
Guo, Y.; Bao, Y.; Ma, M.; Yang, W. Identification of key candidate genes and pathways in colorectal cancer by integrated bioinformatical analysis. Int. J. Mol. Sci., 2017, 18(4), 722.
[19]
Fang, E.; Zhang, X.; Wang, Q.; Wang, D. Identification of prostate cancer hub genes and therapeutic agents using bioinformatics approach. Cancer Biomark., 2017, 20(4), 553-561.
[20]
Zhang, K.; Xu, Z.; Sun, Z. Identification of the key genes connected with plasma cells of multiple myeloma using expression profiles. OncoTargets Ther., 2015, 8, 1795-1803.
[21]
Irizarry, R.A.; Hobbs, B.; Collin, F. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics, 2003, 4(2), 249-264.
[22]
Gautier, L.; Cope, L.; Bolstad, B.M.; Irizarry, R.A. affy--analysis of affymetrix genechip data at the probe level. Bioinformatics, 2004, 20(3), 307-315.
[http://dx.doi.org/10.1093/bioinformatics/btg405] [PMID: 14960456]
[23]
Ritchie, M.E.; Phipson, B.; Wu, D. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res., 2015, 43(7)
[24]
Zhang, B.; Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol., 2005, 4e17
[http://dx.doi.org/10.2202/1544-6115.1128] [PMID: 16646834]
[25]
Chen, J.; Yu, L.; Zhang, S.; Chen, X. Network analysis-based approach for exploring the potential diagnostic biomarkers of acute myocardial infarction. Front. Physiol., 2016, 9(7)
[26]
Langfelder, P.; Zhang, B.; Horvath, S. Defining clusters from a hierarchical cluster tree: The dynamic tree cut package for R. Bioinformatics, 2008, 24(5), 719-720.
[http://dx.doi.org/10.1093/bioinformatics/btm563] [PMID: 18024473]
[27]
Yip, A.M.; Horvath, S. Gene network interconnectedness and the generalized topological overlap measure. BMC Bioinformatics, 2007, 24, 8-22.
[28]
Langfelder, P.; Horvath, S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics, 2008, 29, 8-22.
[29]
Hu, J.; Chen, Z.; Bao, L. Single-Cell transcriptome analysis reveals intratumoral heterogeneity in ccrcc, which results in different clinical outcomes. Mol. Ther., 2020, 28(7), 1658-1672.
[30]
Hänzelmann, S.; Castelo, R.; Guinney, J. GSVA: Gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics, 2013, 14(7), 7.
[http://dx.doi.org/10.1186/1471-2105-14-7] [PMID: 23323831]
[31]
De Bock, K.; Georgiadou, M.; Schoors, S. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell, 2013, 28(7), 1658-1672.
[32]
Del Toro, R.; Prahst, C.; Mathivet, T. Identification and functional analysis of endothelial tip cell-enriched genes. Blood, 2010, 116(19), 4025-4033.
[33]
Strasser, G.A.; Kaminker, J.S.; Tessier-Lavigne, M. Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching. Blood, 2010, 115(24), 5102-5110.
[http://dx.doi.org/10.1182/blood-2009-07-230284] [PMID: 20154215]
[34]
Herbert, S.P.; Stainier, D.Y.R. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat. Rev. Mol. Cell Biol., 2011, 12(9), 551-564.
[http://dx.doi.org/10.1038/nrm3176] [PMID: 21860391]
[35]
Gerhardt, H.; Golding, M.; Fruttiger, M. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J. Cell Biol., 2003, 161(6), 1163-1177.
[36]
Roca, C.; Adams, R.H. Regulation of vascular morphogenesis by Notch signaling. Genes Dev., 2007, 21(20), 2511-2524.
[37]
Liu, Z-J.; Shirakawa, T.; Li, Y. Regulation of notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells implications for modulating arteriogenesis and angiogenesis. Mol. Cell. Biol., 2003, 23(1), 14-25.
[38]
Xiang, Y.; Yao, X.; Wang, X. Houshiheisan promotes angiogenesis via HIF-1α/VEGF and SDF-1/CXCR4 pathways: in vivo and in vitro. Biosci. Rep., 2019, 39(10)
[39]
Zhong, J.; Li, J.; Wei, J. Plumbagin restrains hepatocellular carcinoma angiogenesis by stromal cell-derived factor (SDF-1)/CXCR4-CXCR7 axis. Med. Sci. Monit., 2019, 25, 6110-6119.
[http://dx.doi.org/10.12659/MSM.915782] [PMID: 31415486]
[40]
Zhang, H.; Wang, P.; Zhang, X.; Zhao, W.; Ren, H.; Hu, Z. SDF1/CXCR4 axis facilitates the angiogenesis via activating the PI3K/AKT pathway in degenerated discs. Mol. Med. Rep., 2020, 22(5), 4163-4172.
[http://dx.doi.org/10.3892/mmr.2020.11498] [PMID: 32901877]
[41]
Pitulescu, M.E.; Schmidt, I.; Giaimo, B.D. Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat. Cell Biol., 2017, 19(8), 915-927.
[http://dx.doi.org/10.1038/ncb3555] [PMID: 28714968]
[42]
Roudnicky, F.; Poyet, C.; Wild, P. Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis. Cancer Res., 2013, 73(3), 1097-1106.
[http://dx.doi.org/10.1158/0008-5472.CAN-12-1855] [PMID: 23243026]
[43]
Rennel, E.; Mellberg, S.; Dimberg, A. Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer. Exp. Cell Res., 2007, 313(7), 1285-1294.
[44]
Su, T.; Zhong, Y.; Demetriades, A.M. Endocan blockade suppresses experimental ocular neovascularization in mice. Invest. Ophthalmol. Vis. Sci., 2018, 59(2), 930-939.
[http://dx.doi.org/10.1167/iovs.17-22945] [PMID: 29450540]
[45]
Li, C.; Geng, H.; Ji, L.; Ma, X.; Yin, Q.; Xiong, H. ESM-1: A novel tumor biomaker and its research advances. Anticancer. Agents Med. Chem., 2019, 19(14), 1687-1694.
[http://dx.doi.org/10.2174/1871520619666190705151542] [PMID: 31284875]
[46]
Gaonac’h-Lovejoy Boscher. Delisle Gratton. Rap1 Is involved in angiopoietin-1-induced cell-cell junction stabilization and endothelial cell sprouting. Cells, 2020, 9(1), 155.
[47]
Wang, L.; Liu, W.X.; Huang, X.G. MicroRNA-199a-3p inhibits angiogenesis by targeting the VEGF/PI3K/AKT signalling pathway in an in vitro model of diabetic retinopathy. Exp. Mol. Pathol., 2020, 116(1)104488
[http://dx.doi.org/10.1016/j.yexmp.2020.104488] [PMID: 32622012]

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