Vascular Endothelial Growth Factor Polymorphism in Bladder Cancer: A Review


  • Ginanda Putra Siregar Department of Surgery, Division of Urology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia



Physicochemical properties, Solid dispersion, Irbesartan, Poloxamer 188


Bladder cancer is one of the most common urinary tract cancers. The main risk factors for bladder cancer are tobacco usage, aging, gender, exposure to chemicals and drugs such as cyclophosphamide and chlornaphazine, chronic bladder problems, and genetics. Genetic factors continue to be studied including vascular endothelial growth factor (VEGF) gene polymorphism. Overexpression of VEGF is known to be higher in bladder cancer patient than healthy individual. It is also associated with tumor progression, metastasis, recurrence, and survival since VEGF and its receptor play a key role in angiogenesis. Many studies evaluated the relationship between VEGF polymorphism and the risk of bladder cancer, but the results were inconsistent because of ethnicity and geographical influences. The present study aims to raise knowledge about the role of VEGF polymorphisms on risk of bladder cancer.


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Zhang X, Zhang Y. Bladder cancer and genetic mutations. Cell Biochem Biophys. 2015;73(1):65-9. PMid:27352265

Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27(3):289-93. PMid:19219610

Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RL, et al. Global Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007. p. 1-46.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90. PMid:21296855

Mazdak H, Tolou, Ghamari Z. Preliminary study of prevalence for bladder cancer in Isfahan Province, Iran. Arab J Urol. 2018;16(2):206-10. PMid:29892483

Gulia C, Baldassarra S, Signore F, Rigon G, Pizzuti V, Gaffi M, et al. Role of non-coding RNAs in the etiology of bladder cancer. Genes. 2017;8(11):339. PMid:29165379

Chung KT. The etiology of bladder cancer and its prevention. J Cancer Sci Ther. 2013;5(10):346-61.

Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP. Superficial bladder cancer: An update on etiology, molecular development, classification, and natural history. Rev Urol. 2008;10:31-43. PMid:18470273

Brooks NA, O’Donnell MA. Treatment options in non-muscle-invasive bladder cancer after BCG failure. Indian J Urol. 2015;31:312-9. PMid:26604442

Scarpato KR, Morgans AK, Moses KA. Optimal management of muscle-invasive bladder cancer a review. Res Rep Urol. 2015;7:143-51. PMid:26380230

Cohen SM, Shirai T, Steineck G. Epidemiology and etiology of premalignant and malignant urothelial changes. Scand J Urol Nephrol Suppl. 2000;205:105-15. https://doi.

Siregar. VEGF Polymorphism in Bladder CancerOpen Access Maced J Med Sci. 2020 Mar 05; 8(F):31-36. 35org/10.1080/00365590050509869 PMid:11144890

Zaridze DG. Molecular epidemiology of cancer. Biochemistry. 2008;73:532-42. PMid:18605978

Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: Correlation with variation in VEGF protein production. Cytokine. 2000;12(8):1232-5. PMid:10930302

Wang H, Hartnett ME. Regulation of signaling events involved in the pathophysiology of neovascular AMD. Mol Vis. 2016;22:189-202. PMid: 27013848

Garbuzenko DV, Arefyev NO, Belov DV. Mechanisms of adaptation of the hepatic vasculature to the deteriorating conditions of blood circulation in liver cirrhosis. World J Hepatol. 2016;8:665-72. PMid:27326313

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-76. PMid:12778165

Goebel S, Huang M, Davis WC, Jennings M, Siahaan TJ, Alexander JS, et al. VEGF-A stimulation of leukocyte adhesion to colonic microvascular endothelium: Implications for inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 2006;290:G648-54. PMid:16293653

Wang Y, Chang J, Li YC, Li YS, Shyy JY, Chien S. Shear stress and VEGF activate IKK via the Flk-1/Cbl/Akt signaling pathway. Am J Physiol Heart Circ Physiol. 2004;286:H685-92. PMid:14551058

Benoit T, Keller EX, Wolfsgruber P, Hermanns T, Günthart M, Banzola I, et al. High VEGF-D and low MMP-2 serum levels predict nodal-positive disease in invasive bladder cancer. Med Sci Monit 2015;21:2266-74. PMid:26241709

Fauconnet S, Bernardini S, Lascombe I, Boiteux G, Clairotte A, Monnien F, et al. Expression analysis of VEGF-A and VEGF-B: Relationship with clinicopathologicalparameters in bladder cancer. Oncol Rep. 2009;21:1495-504. PMid:19424629

Kopparapu PK, Boorjian SA, Robinson BD, Downes M, Gudas LJ, Mongan NP, et al. Expression of VEGF and its receptors VEGFR1/VEGFR2 is associated with invasiveness of bladder cancer. Anticancer Res. 2013;33:2381-90 PMid:23749886

Eissa S, Salem AM, Zohny SF, Hegazy MG. The diagnostic efficacy of urinary TGF-β1 and VEGF in bladder cancer: comparison with voided urine cytology. Cancer Biomark. 2007;3:275-85. PMid:18048965

Shibuya M. Vascular endothelial growth factor and its receptor system: Physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153(1):13-9. PMid:23172303

Verma A, Degrado J, Hittelman AB, Wheeler MA, Kaimakliotis HZ, Weiss RM. Effect of mitomycin C on concentrations of vascular endothelial growth factor and its receptors in bladder cancer cells and in bladders of rats intravesically instilled with mitomycin C. BJU Int. 2011;107:1154-61. PMid:20735383

Goodison S, Chang M, Dai Y, Urquidi V, Rosser CJ. A multi-analyte assay for the non-invasive detection of bladder cancer. PLoS One. 2012;7:e47469. PMid:23094052

Shariat SF, Youssef RF, Gupta A, Chade DC, Karakiewicz PI, Isbarn H, et al. Association of angiogenesis-related markers with bladder cancer outcomes and other molecular markers. J Urol. 2010;183:1744-50. PMid:20299037

Bernardini S, Fauconnet S, Chabannes E, Henry PC, Adessi G, Bittard H. Serum levels of vascular endothelial growth factor as a prognostic factor in bladder cancer. J Urol. 2001;166:1275-9. PMid:11547057

Beecken WD, Engl T, Hofmann J, Jonas D, Blaheta R. Clinical relevance of serum angiogenic activity in patients with transitional cell carcinoma of the bladder. J Cell Mol Med. 2005;9(3):655-61. PMid:16202212

Quentin T, Schlott T, Korabiowska M, Käthei N, Zöller G, Glaser F, et al. Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression. Anticancer Res. 2004;24:2745-56. PMid:15517881

Black PC, Dinney CP. Bladder cancer angiogenesis and metastasis-translation from murine model to clinical trial. Cancer Metastasis Rev. 2007;26:623-34.

Miyake H, Hara I, Yamanaka K, Gohji K, Arakawa S, Kamidono S. Elevation of serum level of vascular endothelial growth factor as a new predictor of recurrence and disease progression in patients with superficial urothelial cancer. Urology. 1999;53:302-7. PMid:9933044

Puntoni M, Petrera M, Campora S, Garrone E, Defferrari C, Torrisi R, et al. Prognostic Significance of VEGF after twenty-year follow-up in a randomized trial of fenretinide in non-muscle-invasive bladder cancer. Cancer Prev Res. 2016;9(6):437-44. PMid:27045034

Pinto A, Redondo A, Zamora P, Castelo B, Espinosa E. Angiogenesis as a therapeutic target in urothelial carcinoma. Anticancer Drugs. 2010;21:890-6. PMid:20729712

Kunze D, Wuttig D, Kausch I, Blietz C, Blumhoff L, Burmeister Y, et al. Antisense-mediated inhibition of survivin, hTERT and VEGF in bladder cancer cells in vitro and in vivo. Int J Oncol. 2008;32:1049-56. PMid:18425331

Nakanishi R, Oka N, Nakatsuji H, Koizumi T, Sakaki M, Takahashi M, et al. Effect of vascular endothelial growth factor and its receptor inhibitor on proliferation and invasion in bladder cancer. Urol Int. 2009;83:98-106. PMid:19641368

Rahim NG, Harismendy O, Topol EJ, Frazer KA. Genetic determinants of phenotypic diversity in humans. Genome Biol. 2008;4:215. PMid:18439327.

Jain L, Vargo CA, Danesi R, Sissung TM, Price DK, Venzon D, et al. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors. Mol Cancer Ther. 2009;8(9):2496-508. PMid:19755511.

Corvalan AH, Carrasco G, Saavedra K. The genetic and epigenetic bases of gastritis. In Mozsik G, editor. Current Topics in Gastritis. London: InTech; 2012. p. 79-95.

Barret LW, Fletcher S, Wilton SD. Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell Mol Life Sci. 2012;69(21):3613-34. PMid:22538991.

Goldberg-Cohen I, Furneauxb H, Levy AP. A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR. J Biol Chem. 2002;277(16):13635-40. PMid:11834731

Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E. A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. JVasc Res. 2000;37:443-8. PMid:11146397

Krippl P, Langsenlehner U, Renner W, Yazdani-Biuki B, Wolf G, Wascher TC, et al. A common 936C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer. 2003;106:468-71. PMid:12845639

Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Sivridis E. VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer. 2004;46:293-8. PMid:15541813

Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, et al. A common polymorphism in the 5’- untranslated region of the VEGF gene is associated with diabetic retinopathy in Type 2 diabetes. Diabetes. 2002;51:1635-9. PMid:11978667

Yang Y, Zhang X, Song D, Wei J. Association between vascular endothelial growth factor gene polymorphisms and bladder cancer risk. Mol Clin Oncol. 2014;2:501-5. PMid:24940484

Garcia-Closas M, Malats N, Real FX, Yeager M, Welch R, Silverman D, et al. Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet. 2007;3(2):e29. PMid:17319747.

Fu D, Li P, Cheng W, Tian F, Xu X, Yi X, et al. Impact of vascular endothelial growth factor gene- gene and gene- smoking interaction and haplotype combination on bladder cancer risk in Chinese population. Oncotarget. 2017;8(14):22927-35. PMid:28206971

Jaiswal PK, Tripathi N, Shukla A, Mittal RD. Association of single nucleotide polymorphisms in vascular endothelial growth factor gene with bladder cancer risk. Med Oncol. 2013;30:509. PMid: 23430447

Longo F, Biondi ML, Inneo V, Itri E, Murano M, Pacciolla R, et al. Vascular endothelial growth factor (VEGF) genotypes, halotypes and risk of bladder cancer. Eur Urol Suppl. 2009;8(4):227.

Wafi SB, Kallel A, Fradj MK, Sallemi A, Rhouma SB, Halima MB, et al. Haplotype-based association of vascular endothelial growth factor gene polymorphisms with urothelial bladder cancer risk in Tunisian population. J Clin Lab Anal. 2018;32:e22610. PMid: 29959793

Henriquez-Hernandez LA, Navarro P, Luzardo OP, Alvarez-Leon EE, Boada LD, Zumbado M, et al. Polymorphisms of glutathione S-transferase and, MDR1 and VEGF genes as risk factors of bladder cancer: A case-control study. Urol Oncol. 2012;30(5):660-5. PMid: 21292509

Siregar GA, Parwati I, Achmad TH, Syukriani YF. Association between VEGF-634G>C gene polymorphism with gastric premalignant lesions and serum VEGF levels in Helicobacter pylori gastritis patients. Open Access Maced J Med Sci.




How to Cite

Siregar GP. Vascular Endothelial Growth Factor Polymorphism in Bladder Cancer: A Review. Open Access Maced J Med Sci [Internet]. 2020 Mar. 5 [cited 2022 Dec. 9];8(F):31-6. Available from:



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