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CC BY-NC-ND 4.0 · Arq Neuropsiquiatr 2020; 78(01): 34-38
DOI: 10.1590/0004-282X20190131
ARTICLE

A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

Uma análise abrangente dos genes relacionados à angiogênese no glioblastoma multiforme vs. glioma cerebral de baixo grau
Burcu BITERGE-SUT 
1   Nigde Omer Halisdemir University, Faculty of Medicine, Department of Medical Biology, Nigde, Turkey.
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Abstract

Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

Resumo

Os tumores cerebrais são uma das causas mais comuns de mortes relacionadas ao câncer em todo o mundo. A angiogênese tem caráter crítico em gliomas malignos de alto grau, como o glioblastoma multiforme. Objetivo: O objetivo deste estudo foi analisar comparativamente os genes relacionados à angiogênese, VEGFA, VEGFB, KDR, CXCL8, CXCR1 e CXCR2 em GBG vs. GBM para identificar distinções moleculares usando conjuntos de dados disponíveis no The Cancer Genome Atlas (TCGA). Métodos: Os dados de sequenciamento de DNA e expressão de mRNA para 514 pacientes com glioma cerebral de baixo grau (GBG) e 592 pacientes com glioblastoma multiforme (GBM) foram adquiridos do TCGA e as alterações genéticas e os níveis de expressão dos genes selecionados foram analisados. Resultados: Identificamos seis mutações KDR distintas nos pacientes GBG e 18 mutações KDR distintas nos pacientes GBM, incluindo mutações missense e nonsense, exclusão de mudança de quadro e região de emenda alterada. Além disso, VEGFA e CXCL8 foram significativamente super-expressos nos pacientes com GBM. Conclusões: VEGFA e CXCL8 são fatores importantes para a angiogênese, os quais parecem ter um papel significativo durante a tumorigênese. Nossos resultados fornecem evidências adicionais de que o VEGFA e o CXCL8 podem induzir a angiogênese e promover o GBG a progredir no GBM. Esses achados podem ser úteis no desenvolvimento de novas abordagens terapêuticas direcionadas no futuro.

Keywords:

brain tumor - angiogenesis - genetics

Palavras-chave:

neoplasias encefálicas - angiogênese - genética


Publikationsverlauf

Eingereicht: 06. August 2019

Angenommen: 18. September 2019

Artikel online veröffentlicht:
13. Juni 2023

© 2020. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 McNeill KA. Epidemiology of Brain Tumors. Neurol Clin. 2016 Nov;34(4):981-98. http://dx.doi.org/10.1016/j.ncl.2016.06.014
  • 2 Whittle IR. The dilemma of low grade glioma. J Neurol Neurosurg Psychiatry. 2004;75:Suppl 2:ii31-6. http://dx.doi.org/10.1136/jnnp.2004.040501
  • 3 Claus EB, Walsh KM, Wiencke JK, Molinaro AM, Wiemels JL, Schildkraut JM, et al. Survival and low-grade glioma: the emergence of genetic information. Neurosurg Focus. 2015 Jan;38(1):E6. http://dx.doi.org/10.3171/2014.10
  • 4 Das S, Marsden PA. Angiogenesis in glioblastoma. N Engl J Med. 2013 Oct;369(16):1561-3. http://dx.doi.org/10.1056/NEJMcibr1309402
  • 5 Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017 Nov;20(4):409-26. http://dx.doi.org/10.1007/s10456-017-9562-9
  • 6 Caporarello N, Lupo G, Olivieri M, Cristaldi M, Cambria MT, Salmeri M, et al. Classical VEGF, Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions (Review). Mol Med Rep. 2017 Oct;16(4):4393-402. http://dx.doi.org/10.3892/mmr.2017.7179
  • 7 Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008 Jul;454:436-44.
  • 8 Yeung YT, McDonald KL, Grewal T, Munoz L. Interleukins in glioblastoma pathophysiology: implications for therapy. Br J Pharmacol. 2013 Feb;168(3):591-606. https://doi.org/10.1111/bph.12008
  • 9 Singh S, Wu S, Varney M, Singh AP, Singh RK. CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation. Microvasc Res. 2011 Nov;82(3):318-25. http://dx.doi.org/10.1016/j.mvr.2011.06.011
  • 10 Kargiotis O, Rao JS, Kyritsis AP. Mechanisms of angiogenesis in gliomas. J Neurooncol. 2006 Jul;78(3):281-93. http://dx.doi.org/10.1007/s11060-005-9097-6
  • 11 Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012 Apr;26(5):756-84. http://dx.doi.org/10.1101/gad.187922.112
  • 12 Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012 May;2(5):401-4. http://dx.doi.org/10.1158/2159-8290.CD-12-0095.
  • 13 Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013 Apr;6(269):pl1. http://dx.doi.org/10.1126/scisignal.2004088
  • 14 Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. Cell. 2018 Apr;173(2):400-416.e11. http://dx.doi.org/10.1016/j.cell.2018.02.052
  • 15 Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017 Jul 3;45(W1):W98-W102. http://dx.doi.org/10.1093/nar/gkx247
  • 16 Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013 Oct;155(2):462-77. http://dx.doi.org/10.1016/j.cell.2013.09.034
  • 17 De Keersmaecker K, Atak ZK, Li N, Vicente C, Patchett S, Girardi T, et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat Genet. 2013 Feb;45(2):186-90. http://dx.doi.org/10.1038/ng.2508
  • 18 Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017 Jun;23(6):703-713. http://dx.doi.org/10.1038/nm.4333
  • 19 Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016 Apr;15(4):857-65. http://dx.doi.org/10.1016/j.celrep.2016.03.075
  • 20 Xu Y, Yuan FE, Chen QX, Liu BH. Molecular mechanisms involved in angiogenesis and potential target of antiangiogenesis in human glioblastomas. Glioma. 2018 Apr;1(2):35-42. http://dx.doi.org/10.4103/glioma.glioma_10_17
  • 21 Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpé S, Vermeulen PB, Dirix LY. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res. 2004 Nov;10(21):7157-62. http://dx.doi.org/10.1158/1078-0432.CCR-04-0812
  • 22 Zhang H, Fu T, McGettigan S, Kumar S, Liu S, Speicher D, et al. IL-8 and cathepsin B as melanoma serum biomarkers. Int J Mol Sci. 2011 Feb;12(3):1505-18. http://dx.doi.org/10.3390/ijms12031505
  • 23 Desbaillets I, Diserens AC, Tribolet N, Hamou MF, Van Meir EG. Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. J Exp Med. 1997 Oct;186(8):1201-12. http://dx.doi.org/10.1084/jem.186.8.1201
  • 24 Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res. 2008 Nov;14(21):6735-41. http://dx.doi.org/10.1158/1078-0432.CCR-07-4843