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  • Association of interleukin-17A and chemokine/vascular endothelial growth factor-induced angiogenesis in newly diagnosed patients with bladder cancer

  • elhamzeynali,1 Hossein Khorramdelazad,2,*
    1. Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
    2. Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran


  • Introduction: Bladder cancer (BC) is known as one of the most com- mon types of urinary tract cancer, affecting 40,000 people worldwide every year with a very high mortality rate [1]. Several factors, including smoking habits, work- place exposure, age, gender, and genetics, can contrib- ute to the BC pathophysiology [2]. On the other hand, immune system components and mediators such as immune cells, cytokines, growth factors, and their sub- sequent responses can correspondingly lead to tumor eradication or progression [3, 4]. Cytokines and che- mokines are small glycoproteins involved in numerous immune and non-immune cell biological phenomena [5,6]. These immune mediators can also cause cell growth, proliferation, survival, differentiation, migration, and apoptosis or necrosis [4, 7, 8]. Moreover, cytokines can participate in anti-tumoral responses considering the status of the tumor microenvironment (TME); how- ever, in some pathologic states such as chronic inflam- mation, depending on the balance and concentrations of pro-and anti-inflammatory mediators, the activation state of surrounding cells and expression of their recep- tors, cytokines can be effective in tumor progression [9– 12]. Studies have revealed that among these cytokines, the IL-17 family (IL-17A to IL-17 F) and their receptor (IL-17RA to IL-17RE) are involved in Th17 responses, and they can participate in pro-tumor or anti-tumor responses depending on their phenotype [13]. In addition, it is well known that IL-17A and IL-17 F can bind to IL-17RA and IL-17RC receptors, and these types of ligands and receptors can be involved in cyto- kine release, neutrophil recruitment, inflammation, and vascular endothelial growth factor (VEGF)-associated angiogenesis [14, 15]. Furthermore, IL‑17 A may induce chemokine‑induced angiogenesis (CXCL8/CXCR2 axis) and promote tumor progression independent of the VEGF pathway [16]. As a tumor escape mecha- nism, tumor cells release high levels of transforming growth factor β (TGF-β) and CXCL8 to enhance growth and invasion via inducing angiogenesis [17]. Induc- tion of VEGF by IL-17A stimulates TGF-β production and angiogenesis [18]. Accordingly, this study aimed to explore the role of the IL-17A/IL-17RA/C axis in VEGF- and CXCR2-mediated angiogenesis in patients with BC.
  • Methods: The study was designed as a cross-sectional study and enrolled forty-five male patients with confirmed BC referred to Moradi Hospital affiliated with Rafsanjan Uni- versity of Medical Sciences, Rafsanjan, Iran, from Janu- ary 2022 to November 2022. All the patients had invasive BC (T2-T4) regarding the pathological findings. More- over, forty-two age and gender-matched healthy subjects without a history of urological disorders were enrolled in this study. According to the potential impression of chronic inflammation and taking anti-inflammatory medicines on the outcomes of the study, healthy subjects with severe infections in the last six months, an acute or chronic inflammatory disorder, allergies, asthma, rheu- matoid arthritis (RA), liver cirrhosis, trauma, Crohn’s disease, diabetes, ulcerative colitis, pituitary tumors, multiple sclerosis, urinary tract infections, other malig- nant neoplasia, subjects who might have been exposed to industrial chemicals of aromatic amines such as ben- zidine and beta-naphthylamine were excluded. Addi- tionally, patients with BC who had received the Bacillus Calmette-Guerin (BCG) vaccine or mitomycin were excluded from the study. Tissue and blood samples were taken from all newly diagnosed patients before taking chemotherapy or other anti-cancer treatments. Following physical examination, urological examina- tion, ultrasonography (US) of the bladder, intravenous urography (IVU), and cystoscopy, a definite indication for surgery (transurethral resection-TUR) was given. BC tumoral tissue and adjacent normal tissue samples (bladder epithelial tissues at a distance of over five cm from the edge of tumoral tissues) were obtained [19]. The grade and stage of BC were determined based on the TNM (Tumor Nodules Metastases) classification of malignant tumors and a histopathological examination [20]. All patients had a high grade of BC following his- topathological examination, based on cancer progression potential. The Ethics Committee of Rafsanjan University of Medical Sciences approved the protocol of this study. The informed consent was explained to each participant, and the oral and written consent forms were obtained from patients before the surgery and sample collection.
  • Results: All the subjects (n = 87) were matched in age and gender. A total of 45 patients with BC (mean age of 62.15 ± 11.37 years) and 42 healthy subjects (mean age of 58.55 ± 12.31 years) were enrolled in this study. The mean age in the control group was lower than BC patients, but this differ- ence was not statistically significant (P = 0.32) (Table 2). The data obtained from the RT-PCR showed a sig- nificant upregulation in the expression of IL-17RA (Fig. 1A), IL-17RC (Fig. 1B), and CXCR2 (Fig. 1C), in the tumoral tissue of BC patients compared to normal tissue (p < 0.0001). Moreover, this study revealed a sig- nificant increase in the serum levels of IL-17A in BC patients (12.87 ± 3.26 pg/mL) compared with the control group (95.06 ± 10.55 pg/mL) (p < 0.0001). The difference between the control and BC patients was 328.9 ± 9.582 pg/mL (Fig. 2A). In addition, tissue levels of IL-17A were remarkably higher in BC patients (694.5 ± 76.67 pg/ mL) than in normal tissues (172.3 ± 48.28 pg/mL) with a 522.2 ± 13.85 pg/mL difference between the normal and tumoral tissues (p < 0.0001) (Fig. 2B). Measuring the tis- sue concentrations of VEGF showed that there was a sig- nificant increase in the tissue levels of VEGF in patients with BC (1136 ± 126.2 pg/mL) in comparison with the normal control tissues (99.04 ± 49.27 pg/mL) (P < 000.1) (Fig. 2C). The difference between the mean of tumor and normal tissues in the VEGF test was 1037 ± 20.82 pg/mL. In this study, the tissue levels of TGF-β were measured in normal and tumor tissues of patients with BC. The out- comes revealed a significant elevation in the tissue level of TGF-β in BC patients (808.7 ± 84.64 pg/mL) compared to the normal control tissue (117.6 ± 27.52 pg/mL) with a 691.0 ± 13.69 pg/mL difference between the normal and tumoral tissues (p < 0.0001) (Fig. 2D). 8 The receiver operating characteristic (ROC) curve analysis revealed a promising diagnostic performance for the cutoff value of 123.6 pg/mL, with an impressive area under the ROC curve of 0.9818 (95% CI: 0.9627 to 1.000, p < 0.0001), indicating excellent discrimination between controls (n = 42) and patients (n = 45). There were no missing data for either controls or patients, ensuring the robustness of the analysis. These findings suggest that the proposed cutoff value exhibits high sensitivity and speci- ficity, making it a reliable tool for distinguishing between the two groups in this study (Fig. 3).
  • Conclusion: In conclusion, the present study investigated the expres- sion levels of IL-17RA, IL-17RC, CXCR2, IL-17A, VEGF, and TGF-β in BC patients compared to healthy controls. Significant upregulation was observed in the tumoral tissue of BC patients for IL-17RA, IL-17RC, CXCR2, IL-17A, VEGF, and TGF-β. Moreover, serum and tis- sue levels of IL-17A, as well as VEGF and TGF-β tissue levels, were significantly elevated in BC patients com- pared to controls. These findings indicate the studied mediators could be involved in the pathogenesis of BC. Importantly, the ROC curve analysis demonstrated the promising diagnostic performance of IL-17A, indicat- ing excellent discrimination between BC patients and controls. It suggests that the proposed cutoff value holds high sensitivity and specificity, making it a possible tool for distinguishing between the two groups in this study. However, further investigations with larger sample sizes are needed to confirm the possibility of using serum lev- els of IL-17A as a diagnostic biomarker for patients with BC. These findings suggest the potential of the investi- gated mediators as diagnostic and therapeutic targets.
  • Keywords: IL-17A, CXCR2, VEGF, TGF-Beta, Bladder cancer

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