MMP, VEGF and TIMP as prognostic factors in recurring bladder cancer
Graphical abstract
Introduction
Transurethral resection of BCa (TURB) is standard treatment associated with NMIBC's residual risk. While partial cystectomy is a bladder sparing procedure, it is applied to treat invasive bladder cancer in selected patients [1]. More invasive treatment including combination of TURB with radiotherapy or chemotherapy, which may improve the recurrence-free survival, is of limited applicability, because of the patients' age-related health conditions [2]. Therefore, effective surveillance of BCa and development of efficient predictors of its recurrence are still necessary.
Tumor invasion depends on the remodeling processes that occur in connective tissue extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are the most important extracellular proteases that play a role in degradation and dissolution of ECM and basement membrane [3], [4]. MMPs cooperate in the regulation of proangiogenic factor — vascular endothelial growth factor (VEGF) [5], [6]. The proteolytic activity of MMP enzymes is highly regulated by effective inhibitors — tissue inhibitors of metalloproteinases (TIMPs) [7].
The basement membrane damage and angiogenesis processes involve interactions between various ECM proteins, in which MMPs, VEGFs and TIMPs seem to be most important [8], [9], [10]. Several reports have demonstrated that the expression of MMP, TIMP and VEGF genes is correlated with tumor progression, invasion and angiogenesis of BCa [11], [12], [13], [14], [15], [16]. Despite the evidence of involvement of the MMPs, TIMPs and VEGFs in tumorigenesis and progression of BCa, little is known about their practical usefulness as non-invasive prognostic tools for predicting early recurrence after treatment of BCa. Therefore, we have chosen to investigate whether expression of MMP, TIMP, VEGF genes in peripheral blood leukocytes (PBLs) of BCa patients correlates with clinicopathological features and recurrence. Moreover, we have evaluated the importance of plasma MMP1 levels at diagnosis for prediction of recurrence.
Section snippets
Patients and controls
BCa patients and controls were recruited from the First Department of Urology, Medical University of Lodz and Nofer Institute of Occupational Medicine (NIOM) (Lodz, Poland). Blood samples from BCa patients were collected between 2005–2011. From this group, we selected forty patients with TURB or partial cystectomy and with recurrence. A total of the 100 age-matched controls were recruited between 2011–2012 (Fig. 1). None of the BCa patients showed evidence of any other malignancies at the time
Subject characteristics
One hundred forty individuals (40 BCa patients and 100 controls) were included in the study. Baseline clinical characteristics of BCa patients at diagnosis and controls are shown in Supplementary Table 2. There were no statistically significant differences between the BCa patients and controls for sex and age distribution (p = 0.815 and p = 0.151, respectively). Comparison of body mass index (BMI), indicated that controls were more obese than BCa patients at diagnosis (p = 0.001). There were
Discussion
In this study we analyzed expression of MMP1, MMP2, MMP9, VEGFA and TIMP1, TIMP3 genes in PBLs as potential prognostic factors for recurrence after TURB or partial cystectomy in BCa patients. We also attempted to determine the plasma MMP1 levels and clinical characteristics of BCa in relation to recurrence. To the best of our knowledge, the use of the expression of these genes for the evaluation of recurrence in BCa patients after TURB or partial cystectomy has not been previously performed.
Conflict of interest
None declared.
Acknowledgments
This work was supported by Nofer Institute of Occupational Medicine (internal grant No. 1.22/2013) and the Polish Society of Urology (No. 01/2012).
References (39)
- et al.
Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: a contemporary review of the M. D. Anderson Cancer Center experience
J. Urol.
(2006) - et al.
The role of matrix metalloproteinase MMP-9 and TIMP-2 tissue inhibitor of metalloproteinases as serum markers of bladder cancer
Actas Urol. Esp.
(2013) - et al.
EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines
Eur. Urol.
(2014) - et al.
Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature
Matrix Biol.
(2015) - et al.
The clinical implications of MMP-11 and CK-20 expression in human breast cancer
Clin. Chim. Acta
(2010) - et al.
The peripheral blood transcriptome dynamically reflects system wide biology: a potential diagnostic tool
J. Lab. Clin. Med.
(2006) - et al.
mRNA expression of matrix metalloproteases and their inhibitors differs in subtypes of renal cell carcinomas
Eur. J. Cancer
(2001) - et al.
Matrix metalloproteinase expression in the recurrence of superficial low grade bladder transitional cell carcinoma
J. Urol.
(2007) - et al.
Body mass index (BMI) and mutations of tumor suppressor gene p53 (TP53) in patients with urinary bladder cancer
Urologic Oncology: Seminars and Original Investigations
(2008) - et al.
Detection and molecular staging of bladder cancer using real-time RT-PCR for gelatinases (MMP-2, MMP-9) and TIMP-2 in peripheral blood
Actas Urol. Esp.
(2011)
Significance of matrix metalloproteinases and tissue inhibitors of metalloproteinase expression in the recurrence of superficial transitional cell carcinoma of the bladder
J. Urol.
Age and comorbidity impact surgical therapy in older bladder carcinoma patients: a population-based study
Cancer
New and paradoxical roles of matrix metalloproteinases in the tumor microenvironment
Front. Pharmacol.
Matrix metalloproteinases: protective roles in cancer
J. Cell. Mol. Med.
Vegf targets the tumour cell
Nat. Rev. Cancer
Vascular endothelial growth factor and the regulation of angiogenesis
Recent Prog. Horm. Res.
Tissue inhibitors of metalloproteinases
Genome Biol.
Matrix metalloproteinases and tumor metastasis
Cancer Metastasis Rev.
Matrix metalloproteinases and their clinical relevance in urinary bladder cancer
Nat. Rev. Urol.
Cited by (20)
Differential Expression of Renin-Angiotensin System-related Components in Patients with Rheumatoid Arthritis and Osteoarthritis
2020, American Journal of the Medical SciencesCitation Excerpt :The results showed that there was a significant positive correlation between the level of MMP-14 and VEGF (Pearson = 0.3; P = 0.032), suggesting that MMP-14 was involved in angiogenesis in proliferative diabetic retinopathy. Another study by Wieczorek et al46 showed that the expression of MMP-9 in peripheral blood leukocytes of patients with bladder cancer was related to the degree of differentiation and smoking status in bladder cancer, and the gene expression of MMP-9 and VEGF in peripheral blood leukocytes may play a key role in regulating the progression of bladder cancer. The above results indicate that the increase in RAS-related components in patients with RA and OA may potentially stimulate the expression of VEGF and promote angiogenesis in cartilage and ECM, thus accelerating the degradation of cartilage and ECM.
Intracerebral matrix metalloproteinase 9 in fatal diabetic ketoacidosis
2019, Experimental and Molecular PathologyCitation Excerpt :MMP9 is one of the few MMPs enzymes that are constitutively expressed. It has a diverse spectrum of activity: 1) degrades tight junction proteins and all components of the extracellular matrix proteins including laminin, collagen and fibronectin (Feng et al., 2011); 2) facilitates leukocyte migration and invasion (Lavini-Ramos et al., 2017); 3) integration of immunoregulatory pathways (Lavini-Ramos et al., 2017); 4) maintenance of tissue barriers by processing a range of non-matrix proteins, including cytokines and chemokines (Van Lint and Libert, 2007; Nissinen and Kahari, 2014; Smigiel and Parks, 2017); and 5) staging serum and tissue in metastatic conditions (Wieczorek et al., 2015). They are also involved in the pathogenesis of acute complications such as acute coronary syndromes (Suzuki et al., 2006).
RASAL2 inhibits tumor angiogenesis via p-AKT/ETS1 signaling in bladder cancer
2018, Cellular SignallingCitation Excerpt :Mechanistically, many factors contributed to tumor angiogenesis, such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and matrix metalloproteinases (MMPs) [4,20]. Among them, the family of VEGF, which contained VEGFA, VEGFB, VEGFC and others, was the main mediator in the angiogenesis of different cancer types [21,22], including BCa [23–25]. In our previous study, we have reported VEGFA as the critical mediator of KLF5-regulated BCa angiogenesis.
Matrine inhibits bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway: An experimental study
2017, Asian Pacific Journal of Tropical MedicineCitation Excerpt :The activation of PI3K/AKT signaling pathway can on the one hand, directly start the expression of MMP2, MMP9 and other invasion-related genes, and promote cells invasion [15,16], and on the other hand, can also block the AMP-activated protein kinase activity, inhibit the expression of a variety of tumor suppressor genes and cell cycle-inhibiting molecules and promote cell proliferation [17]. p16, p21 and p27 are the cell cycle-inhibiting molecules that play an important role in the progression of malignant tumors, and they can be combined with a variety of cyclin and cyclin-related protein kinase to hinder the process of cell cycle and thereby inhibit cell proliferation [18]; MMP2 and MMP9 are the important members of the matrix metalloproteinase family that can degrade type Ⅳ collagen, laminin, elastin and various other components in the extracellular matrix and basement membrane, and the MMP2 and MMP9 secreted by cancer cells can promote cells to break through the limit of basement membrane and invade the nearby tissue [19,20]. In the study, analysis of the expression of above proliferation and invasion-related genes showed that different dose of matrine could increase p16, p21 and p27 expression while decrease MMP2 and MMP9 expression in dose-dependent manner.
The promoting effects of GPR176 expression on proliferation, chemoresistance, lipogenesis and invasion of oesophageal cancer
2023, Journal of Cancer Research and Clinical Oncology