The Role of MMP-9 and VEGF in the Invasion State of Bladder Urothelial Carcinoma

Novalia Chumaladewi Guntarno, Anny Setijo Rahaju, Nila Kurniasari


BACKGROUND: Bladder cancer is the tenth-most common cancer in worldwide and the majority are urothelial carcinomas. The depth of invasion plays important role in the prognostic and therapeutic factor in urothelial carcinomas. The expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) may associated with the progression of bladder carcinoma, such as depth of invasion. In this study, the correlation between these two markers in urothelial bladder carcinoma invasion will be analyzed.

METHODS: An analytical observational research with cross-sectional were conducted on 54 formalin fixed paraffin-embedded tissue from radical cystectomy (RC) which were diagnosed as bladder urothelial carcinoma at the Anatomical Pathology Laboratory of Dr. Soetomo Academic Hospital, Surabaya and divided based on the T stage were immunostained using VEGF and MMP-9 monoclonal antibodies. The difference of VEGF and MMP-9 expression in T stage of bladder urothelial carcinoma were analyzed using Kruskal-Wallis and Anova test, the correlation between VEGF and MMP-9 expression in various T stage of bladder urothelial carcinoma were analyzed using Spearman test.

RESULTS: This study showed no significant difference of VEGF expression among T stage of bladder urothelial carcinoma (p>0.05) but there was significant difference of MMP-9 expression in T stage of bladder urothelial carcinoma (p=0.043). There was a correlation between VEGF and MMP-9 in various T stage of bladder urothelial carcinoma (rs= 0.50, p=0.001).

CONCLUSION: The significant correlation of VEGF and MMP-9 expression in bladder urothelial carcinoma may prove the synergistically role of both proteins in tumor invasion by MMP-9 degradation extracellular matrix.

KEYWORDS: urothelial carcinoma, VEGF, MMP-9, T stage

Full Text:



Bray F, Ferlay J, Soerjomataram I, Siegel R, Torre L, Jemal A. Global cancer statistics 2018 : GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin. 2018; 68: 394-424, CrossRef.

Giridhar KV, Kohli M. Management of muscle-invasive urothelial cancer and the emerging role of immunotherapy in advanced urothelial cancer. Mayo Clin Proc. 2017; 92: 1564-82, CrossRef.

Tanaka MF, Sonpavde G. Diagnosis and management of urothelial carcinoma of the bladder diagnosis and management of urothelial carcinoma of the bladder. J Postgrad Med. 2015; 123: 43-55, CrossRef.

Zhao M, He XL, Teng XD. Understanding the molecular pathogenesis and prognostics of bladder cancer : an overview. Chin J Cancer Res. 2016; 28: 92-8, CrossRef.

Inamura K. Bladder cancer: new insights into its molecular pathology. Cancers. 2018; 10: 100, CrossRef.

Magers MJ, Lopez‐Beltran A, Montironi R, Williamson SR, Kaimakliotis HZ, Cheng L. Staging of bladder cancer. Histopathology. 2019; 74: 112-34, CrossRef.

Magalhaes A, Dias S. Angiogenesis–vessels recruitment by tumor cells. In: Fior R, Zilhão R, editors. Molecular and Cell Biology of Cancer. Freiburg: Springer Nature; 2019. p.141-57, CrossRef.

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.

Bronsert P, Werner M. Pathology of Tumor Angiogenesis. Freiburg: Springer Nature; 2018.

Fus LP, Gornicka B. Role of angiogenesis in urothelial bladder carcinoma. Cent European J Urol. 2016; 69: 258-63, CrossRef.

Amalinei C, Caruntu ID, Giuşca SE, Balan RA. Matrix metalloproteinases involvement in pathologic conditions. Rom J Morphol Embryol. 2010; 51: 215-28, PMID.

Gunes M, Kemik AS, Pirincci N, Gecit I, Taken K, Yuksel MB, et al. Preoperative levels of matrix metalloproteinase-7 and-9 and tissue inhibitor of matrix metalloproteinase-1 relation to pathologic parameters in bladder carcinoma patients. Asian Pac J Cancer Prev. 2013; 14: 873-6, CrossRef.

Al-Bassam SSA, Kadhim HS, Khashman BM. Possible association of vascular endothelial growth factor with grades of breast cancer. Int J Res Pharm Chem. 2014; 4: 291-3, article.

Ali HH, Ibraheem MH, Alhindawi MM. Immunohistochemical expression of matrix metalloproteinase-9 in urothelial carcinoma of urinary bladder. Kasr Al Ainy Med J. 2018; 24: 109-14, CrossRef.

Wang F, Xu P, Xie KC, Chen XF, Li CY, Huang Q. Effects of tumor microenviromental factors on VEGF expression. Biomed Rep. 2013; 1: 539-44, CrossRef.

Deniz H, Karakök M, Yagcı F, Güldür ME. Evaluation of relationship between HIF-1α immunoreactivity and stage, grade, angiogenic profile and proliferative index in bladder urothelial carcinomas. Int Urol Nephrol. 2010; 42: 103-7, CrossRef.

Yang Y, Sun M, Wang L, Jiao B. HIFs, angiogenesis, and cancer. J Cell Biochem. 2013; 114: 967-74, CrossRef.

Reis ST, Leite KRM, Piovesan LF, Pontes-Junior J, Viana NI, Abe DK, et al. Increased expression of MMP-9 and IL-8 are correlated with poor prognosis of bladder cancer. BMC Urol. 2012; 12: 18, CrossRef.

Tang Z, Tang C, Juanfen MO, Ying X. Role of MMPs expression in the invasion and metastasis of bladder cancer. Chin J Primary Med Pharm. 2018; 25: 156-60, CrossRef.

Wu GJ, Bao JS, Yue ZJ, Zeng FC, Cen S, Tang ZY, et al. Elevated expression of matrix metalloproteinase-9 is associated with bladder cancer pathogenesis. J Cancer Res Ther. 2018; 14: 54-9, CrossRef.

Huang H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors. 2018; 18: 3249, CrossRef.

Vandooren J, Van den Steen PE, Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol. 2013; 48: 222-72, CrossRef.

Conlon GA, Murray GI. Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol. 2019; 247: 629-40, CrossRef.

Wijayanti E, Fauzyah D. Correlation between VEGF and MMP-9 expression in retinoblastoma extraocular invasion. Majalah Patologi Indonesia. 2017; 26: 44-9, article.

Quintero-Fabián S, Arreola R, Becerril-Villanueva E, Torres-Romero JC, Arana-Argáez VE, Lara-Riegos J, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol. 2019; 9: 1370, CrossRef.


Copyright (c) 2021 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


Indexed by:






The Prodia Education and Research Institute