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Di Spirito A, Balkhi S, Vivona V, Mortara L. Key immune cells and their crosstalk in the tumor microenvironment of bladder cancer: insights for innovative therapies. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002304. [PMID: 40177538 PMCID: PMC11964778 DOI: 10.37349/etat.2025.1002304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 02/27/2025] [Indexed: 04/05/2025] Open
Abstract
Bladder cancer (BC) is a heterogeneous disease associated with high mortality if not diagnosed early. BC is classified into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), with MIBC linked to poor systemic therapy response and high recurrence rates. Current treatments include transurethral resection with Bacillus Calmette-Guérin (BCG) therapy for NMIBC and radical cystectomy with chemotherapy and/or immunotherapy for MIBC. The tumor microenvironment (TME) plays a critical role in cancer progression, metastasis, and therapeutic efficacy. A comprehensive understanding of the TME's complex interactions holds substantial translational significance for developing innovative treatments. The TME can contribute to therapeutic resistance, particularly in immune checkpoint inhibitor (ICI) therapies, where resistance arises from tumor-intrinsic changes or extrinsic TME factors. Recent advancements in immunotherapy highlight the importance of translational research to address these challenges. Strategies to overcome resistance focus on remodeling the TME to transform immunologically "cold" tumors, which lack immune cell infiltration, into "hot" tumors that respond better to immunotherapy. These strategies involve disrupting cancer-microenvironment interactions, inhibiting angiogenesis, and modulating immune components to enhance anti-tumor responses. Key mechanisms include cytokine involvement [e.g., interleukin-6 (IL-6)], phenotypic alterations in macrophages and natural killer (NK) cells, and the plasticity of cancer-associated fibroblasts (CAFs). Identifying potential therapeutic targets within the TME can improve outcomes for MIBC patients. This review emphasizes the TME's complexity and its impact on guiding novel therapeutic approaches, offering hope for better survival in MIBC.
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Affiliation(s)
- Anna Di Spirito
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Sahar Balkhi
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Veronica Vivona
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Lorenzo Mortara
- Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy
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Ohadian Moghadam S, Menbary Oskouie I, Amini E, Momeni SA, Haddad M, Kasaeian A, Nowroozi MR. Prognostic Factors for Intravesical Recurrence in NMIBC: Evaluating the Role of Pyuria, Bacteriuria, and Comorbidities. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2025; 18. [DOI: https:/doi.org/10.5812/ijcm-151782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
Background: The discovery of risk factors that might predict the recurrence of non-muscle invasive bladder cancer (NMIBC) is essential. Objectives: Therefore, this prospective cohort study aimed at examining the association between bacteriuria and pyuria before bacillus Calmette-Guérin (BCG) installation and the occurrence of intravesical recurrence (IVR) in patients diagnosed with NMIBC. Methods: A total of 73 NMIBC patients undergoing transurethral resection of bladder tumor (TURBT) and BCG treatment were included. Pre-instillation urine samples were analyzed for pyuria and bacteriuria. Results: The findings of this study indicated that preoperative pyuria was present in 31 (42.5%) of the studied patients. Furthermore, a statistically significant association was detected between preoperative pyuria and preoperative proteinuria (P < 0.001), preoperative hematuria (P = 0.023), preoperative bacteriuria (P = 0.001), and muscle invasion (MI) (P = 0.028). The results of the univariate analysis indicated substantial associations between the variables of smoking, diabetes, carcinoma in situ (CIS), age, and IVR. Subsequently, a multivariate analysis indicated that diabetes (HR = 18.11, P = 0.004) and CIS (HR = 14.69, P = 0.039) had a statistically significant link with IVR. Conclusions: In conclusion, our study demonstrated that diabetes, CIS, and younger age were the sole independent prognostic factors for IVR. Furthermore, no statistically significant association was observed between pyuria, bacteriuria, and smoking with bladder tumor recurrence. The analyses revealed that pyuria emerged as a statistically significant predictive factor for IVR only among individuals without pre-instillation proteinuria.
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Ohadian Moghadam S, Menbary Oskouie I, Amini E, Momeni SA, Haddad M, Kasaeian A, Nowroozi MR. Prognostic Factors for Intravesical Recurrence in NMIBC: Evaluating the Role of Pyuria, Bacteriuria, and Comorbidities. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2025; 18. [DOI: 10.5812/ijcm-151782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
Background: The discovery of risk factors that might predict the recurrence of non-muscle invasive bladder cancer (NMIBC) is essential. Objectives: Therefore, this prospective cohort study aimed at examining the association between bacteriuria and pyuria before bacillus Calmette-Guérin (BCG) installation and the occurrence of intravesical recurrence (IVR) in patients diagnosed with NMIBC. Methods: A total of 73 NMIBC patients undergoing transurethral resection of bladder tumor (TURBT) and BCG treatment were included. Pre-instillation urine samples were analyzed for pyuria and bacteriuria. Results: The findings of this study indicated that preoperative pyuria was present in 31 (42.5%) of the studied patients. Furthermore, a statistically significant association was detected between preoperative pyuria and preoperative proteinuria (P < 0.001), preoperative hematuria (P = 0.023), preoperative bacteriuria (P = 0.001), and muscle invasion (MI) (P = 0.028). The results of the univariate analysis indicated substantial associations between the variables of smoking, diabetes, carcinoma in situ (CIS), age, and IVR. Subsequently, a multivariate analysis indicated that diabetes (HR = 18.11, P = 0.004) and CIS (HR = 14.69, P = 0.039) had a statistically significant link with IVR. Conclusions: In conclusion, our study demonstrated that diabetes, CIS, and younger age were the sole independent prognostic factors for IVR. Furthermore, no statistically significant association was observed between pyuria, bacteriuria, and smoking with bladder tumor recurrence. The analyses revealed that pyuria emerged as a statistically significant predictive factor for IVR only among individuals without pre-instillation proteinuria.
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Hu L, Wu N, Wang J, Yao M, Han B. Network Pharmacology Combined with Bioinformatics Analysis to Texplore the Potential Mechanism of Phellodendri Chinensis Cortex Against Bladder Cancer. Cell Biochem Biophys 2024; 82:3317-3331. [PMID: 39023680 DOI: 10.1007/s12013-024-01414-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2024] [Indexed: 07/20/2024]
Abstract
The pharmacological mechanism of Phellodendri Chinensis cortex (PCC) against diseases, especially bladder cancer (BC), has never been reported systematically. This study was designed to explore potential mechanism of PCC in treatment of BC. First, we used network pharmacology to discover the potential mechanism of Phellodendri Chinensis cortex and phellodendrine against bladder cancer. Then, we used bioinformatics analysis to verify the correlation between gene expression analysis, survival analysis and common targets. Finally, molecular docking was used to calculate the binding energies of phellodendrine and common targets.A total of 264 targets for PCC were predicted, and 391 BC-related targets were obtained from 4 databases. There were 54 potential targets, 315 biological processes, and 120 signaling pathways involved for PCC against BC. The CDKN2A expression increased and the ESR1, JUN, IL6, AR, and PTGS2 levels decreased in BC according to Gene Expression Profiling Interactive Analysis version 2. The high expression of JUN, MYC, EGFR, and EGF and low expression of VEGFA and PPARG were associated with short overall survival (OS). The high expression of AKT1, EGFR, and EGF and low expression of IL1β were associated with poor disease-free survival (DFS). The search of the intersection of phellodendrine and BC targets yielded 11 common targets, 50 biological processes, and 13 signaling pathways involved. High AURKA and FASN and low ESR1, JUN, ABCB1, and PTGS1 were expressed in BC. The high expression of FASN, ABCC1, PTGS1, JUN, and PIK3CA was associated with short OS, the high expression of PIK3CA and ABCC1 was associated with poor DFS prognosis. Phellodendrine showed a better binding affinity for PTGS2 protein with a docking score of -7.183 and a MM-GBSA result of -46.47 kcal/mol. This study revealed potential mechanism of PCC and phellodendrine against BC through network pharmacology and bioinformatics.
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Affiliation(s)
- Lili Hu
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, 030619, China.
- Shanxi Di'an Medical Inspection Center Co., Ltd., Taiyuan, 030006, China.
| | - Na Wu
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, 030619, China
| | - Jue Wang
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, 030619, China
| | - Mingze Yao
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Bo Han
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
- College of Basic Medicine, Shanxi University of Chinese Medicine, Jinzhong, 030619, China.
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Singh A, Khanna T, Mahendru D, Kahlon J, Kumar V, Sohal A, Yang J. Insights into renal and urological complications of inflammatory bowel disease. World J Nephrol 2024; 13:96574. [PMID: 39351187 PMCID: PMC11439091 DOI: 10.5527/wjn.v13.i3.96574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 07/01/2024] [Accepted: 07/15/2024] [Indexed: 09/19/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic condition characterized by immune-mediated inflammation in the gastrointestinal tract, which follows a relapsing and remitting course. Apart from affecting the gastrointestinal tract, IBD also has extra-intestinal manifestations (EIMs). While the etiology of extraintestinal manifestation remains unclear, it is theorized to be based on immunological responses influenced by genetic factors. Renal involvement is one of the EIMs observed in ulcerative colitis and Crohn's disease. The renal manifestations in IBD patients encompass a range of conditions including nephrolithiasis, amyloidosis, tubulointerstitial nephritis, glomerulonephritis (GN), obstructive pathologies, and chronic kidney disease (CKD). The incidence of CKD in IBD patients varies from 5%-15%. The decline in renal function can stem from various factors such as direct inflammatory damage to the kidneys leading to glomerular or tubular injury, or from complications like recurrent stones, amyloidosis, or GN. Additionally, nephrotoxic medications used in treating IBD, such as TNF-α inhibitors, calcineurin inhibitors, and aminosalicylates, can exacerbate the decline in renal function. Currently, there is a lack of consensus regarding these patients' screening and renal function monitoring. This review aims to assess the existing literature on the different renal complications among individuals with IBD, shedding light on their pathophysiology and management.
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Affiliation(s)
- Anmol Singh
- Department of Medicine, Tristar Centennial Medical Center, Nashville, TN 37203, United States
| | - Tejasvini Khanna
- Department of Medicine, Maulana Azad Medical College, New Delhi 110002, India
| | - Diksha Mahendru
- Department of Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Jasraj Kahlon
- Department of Internal Medicine, Abrazo Medical Center, Phoenix, AZ 85015, United States
| | - Vikash Kumar
- Department of Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, United States
| | - Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, WA 98105, United States
| | - Juliana Yang
- Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX 77555, United States
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Miyakawa J, Yamada Y, Hakozaki Y, Makino K, Kamei J, Taguchi S, Kawai T, Akiyama Y, Yamada D, Kume H. Comparison of PDD-TURBT alone versus white light TURBT plus intravesical BCG therapy: A propensity-score matching study. Photodiagnosis Photodyn Ther 2024; 48:104254. [PMID: 38901718 DOI: 10.1016/j.pdpdt.2024.104254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 06/03/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024]
Abstract
BACKGROUND Although photodynamic-diagnosed transurethral resection of bladder cancer (PDD-TURBT) and Bacillus Calmette-Guérin (BCG) intravesical instillation are the two representative therapies for non-muscle invasive bladder cancer (NMIBC), no studies directly compare their efficacy. We evaluated the outcome of PDD-TURBT alone compared with white light TURBT with intravesical BCG therapy and analyzed the efficacy of both therapies depending on the characteristics of the tumors. METHODS We retrospectively analyzed intermediate- and high-risk NMIBC patients treated with PDD-TURBT alone (the PDD group) or white light TURBT with BCG therapy (the white light group) using propensity score matched analysis. RESULTS In the propensity score matched cohort, the 1-, 2-, and 3-year recurrence-free survival rates for the PDD group were 77.6 %, 64.1 %, and 48.1 %, respectively, compared to 84.6 %, 75.1 %, and 75.1 % for the white light group (p = 0.44, 0.27, 0.17, respectively). The difference in recurrence rates between the two groups tended to become more pronounced over time, although there was no significant difference. In the univariate and multivariate analysis, recurrence, multiplicity, and tumor grade were the significant prognostic factors of recurrence in the PDD group (p = 0.010, 0.047, 0.048, respectively). Long-term RFS was similar in the PDD and white light groups when the population was limited to the primary and single tumors, suggesting that PDD-TURBT alone may be sufficient in this spectrum of patients. CONCLUSIONS PDD-TURBT alone is insufficient to control the long-term recurrence of bladder cancer but can be effective in selected cases such as primary and single tumors.
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Affiliation(s)
- Jimpei Miyakawa
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan; Department of Urology, Kyorin University School of Medicine, Tokyo, Japan
| | - Yuta Yamada
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan.
| | - Yuji Hakozaki
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Katsuhiro Makino
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Jun Kamei
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Satoru Taguchi
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Taketo Kawai
- Department of Urology, Teikyo University School of Medicine, Tokyo, Japan
| | - Yoshiyuki Akiyama
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Daisuke Yamada
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
| | - Haruki Kume
- Department of Urology, Graduate School of Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
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Wu C, Wei X, Huang Z, Zheng Z, Zhang W, Chen J, Hong H, Li W. Urinary microbiome dysbiosis is associated with an inflammatory environment and perturbed fatty acids metabolism in the pathogenesis of bladder cancer. J Transl Med 2024; 22:628. [PMID: 38970045 PMCID: PMC11227203 DOI: 10.1186/s12967-024-05446-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/27/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Bladder cancer is a common malignancy with high recurrence rate. Early diagnosis and recurrence surveillance are pivotal to patients' outcomes, which require novel minimal-invasive diagnostic tools. The urinary microbiome is associated with bladder cancer and can be used as biomarkers, but the underlying mechanism is to be fully illustrated and diagnostic performance to be improved. METHODS A total of 23 treatment-naïve bladder cancer patients and 9 non-cancerous subjects were enrolled into the Before group and Control group. After surgery, 10 patients from the Before group were further assigned into After group. Void mid-stream urine samples were collected and sent for 16S rDNA sequencing, targeted metabolomic profiling, and flow cytometry. Next, correlations were analyzed between microbiota, metabolites, and cytokines. Finally, receiver operating characteristic (ROC) curves of the urinary biomarkers were plotted and compared. RESULTS Comparing to the Control group, levels of IL-6 (p < 0.01), IL-8 (p < 0.05), and IL-10 (p < 0.05) were remarkably elevated in the Before group. The α diversity of urine microbiome was also significantly higher, with the feature microbiota positively correlated to the level of IL-6 (r = 0.58, p < 0.01). Significant differences in metabolic composition were also observed between the Before and Control groups, with fatty acids and fatty acylcarnitines enriched in the Before group. After tumor resection, cytokine levels and the overall microbiome structure in the After group remained similar to that of the Before group, but fatty acylcarnitines were significantly reduced (p < 0.05). Pathway enrichment analysis revealed beta-oxidation of fatty acids was significantly involved (p < 0.001). ROC curves showed that the biomarker panel of Actinomycetaceae + arachidonic acid + IL-6 had superior diagnostic performance, with sensitivity of 0.94 and specificity of 1.00. CONCLUSIONS Microbiome dysbiosis, proinflammatory environment and altered fatty acids metabolism are involved in the pathogenesis of bladder cancer, which may throw light on novel noninvasive diagnostic tool development.
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Affiliation(s)
- Cen Wu
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Xiaoyu Wei
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Zhiyang Huang
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Zhixiong Zheng
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Wei Zhang
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Jiajun Chen
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Hongchang Hong
- Department of Urology, Fujian Medical University Affiliated Quanzhou First Hospital, Fujian, 362011, China
| | - Weili Li
- Zhangjiang Center for Translational Medicine, Shanghai Biotecan Biotechnology Co., Ltd., 180 Zhangheng Road, Pudong District, Shanghai, 201204, China.
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Kayar R, Bastug Y, Tokuc E, Topaktas R, Akyurek EA, Kayar K, Artuk I, Ozturk M. Pan-immune-inflammation value as a prognostic tool for overall survival and disease-free survival in non-metastatic muscle-invasive bladder cancer. Int Urol Nephrol 2024; 56:509-518. [PMID: 37773579 DOI: 10.1007/s11255-023-03812-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/14/2023] [Indexed: 10/01/2023]
Abstract
PURPOSE To evaluate the association between preoperative pan-immune inflammation value (PIV) and overall survival (OS) and disease-free survival (DFS) in patients who underwent radical cystectomy for non-metastatic muscle-invasive bladder cancer. METHODS A total of 119 patients with non-metastatic muscle-invasive bladder cancer who underwent radical cystectomy at our institution between January 2014 and January 2022 were included in this retrospective study. PIV was calculated using the formula (monocyte count × neutrophil count × platelet count)/lymphocyte count. Ideal cut-off values for PIV were determined using ROC curve analysis. Kaplan-Meier analysis was used to evaluate the impact of PIV on survival outcomes. RESULTS The mean age of patients was 65 ± 14 years, and the mean follow-up duration was 36 months. The ideal cutoff value for PIV was determined to be 406.29, and a PIV above this value was associated with poorer OS (p < 0.001) (73 months vs. 21 months) and DFS (p = 0.002) (35 months vs 19 months). Higher neutrophil-to-lymphocyte ratio (NLR) values were also associated with poorer OS (p < 0.001) and DFS (p < 0.001), with similar effectiveness to PIV. PIV was found to be significantly more effective than platelet-to-lymphocyte ratio (PLR) and systemic immune inflammation index (SII) in predicting DFS. CONCLUSION Preoperative PIV may serve as an independent prognostic factor for OS in patients who undergo radical cystectomy with non-metastatic muscle-invasive bladder cancer. A high PIV value was associated with poorer survival outcomes. Prospective multicenter studies are needed to further validate the relationship between PIV and histopathological features of bladder cancer.
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Affiliation(s)
- Ridvan Kayar
- Department of Urology, University of Health Sciences, Haydarpasa Numune SUAM, Tıbbiye Str. No: 40, Uskudar, Istanbul, Turkey
| | - Yavuz Bastug
- Department of Urology, University of Health Sciences, Haydarpasa Numune SUAM, Tıbbiye Str. No: 40, Uskudar, Istanbul, Turkey
| | - Emre Tokuc
- Department of Urology, University of Health Sciences, Haydarpasa Numune SUAM, Tıbbiye Str. No: 40, Uskudar, Istanbul, Turkey.
| | - Ramazan Topaktas
- Department of Urology, University of Health Sciences, Haydarpasa Numune SUAM, Tıbbiye Str. No: 40, Uskudar, Istanbul, Turkey
| | - Elif Atag Akyurek
- Faculty of Medicine, Department of Medical Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Kemal Kayar
- Urology Clinic, Kilis Prof.Dr. Alaeddin Yavasca State Hospital, Kilis, Turkey
| | - Ilker Artuk
- Department of Urology, University of Health Sciences, Haydarpasa Numune SUAM, Tıbbiye Str. No: 40, Uskudar, Istanbul, Turkey
| | - Metin Ozturk
- Department of Urology, University of Health Sciences, Haydarpasa Numune SUAM, Tıbbiye Str. No: 40, Uskudar, Istanbul, Turkey
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Fang ZX, Chen WJ, Wu Z, Hou YY, Lan YZ, Wu HT, Liu J. Inflammatory response in gastrointestinal cancers: Overview of six transmembrane epithelial antigens of the prostate in pathophysiology and clinical implications. World J Clin Oncol 2024; 15:9-22. [PMID: 38292664 PMCID: PMC10823946 DOI: 10.5306/wjco.v15.i1.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/24/2023] [Accepted: 12/19/2023] [Indexed: 01/23/2024] Open
Abstract
Chronic inflammation is known to increase the risk of gastrointestinal cancers (GICs), the common solid tumors worldwide. Precancerous lesions, such as chronic atrophic inflammation and ulcers, are related to inflammatory responses in vivo and likely to occur in hyperplasia and tumorigenesis. Unfortunately, due to the lack of effective therapeutic targets, the prognosis of patients with GICs is still unsatisfactory. Interestingly, it is found that six transmembrane epithelial antigens of the prostate (STEAPs), a group of metal reductases, are significantly associated with the progression of malignancies, playing a crucial role in systemic metabolic homeostasis and inflammatory responses. The structure and functions of STEAPs suggest that they are closely related to intracellular oxidative stress, responding to inflammatory reactions. Under the imbalance status of abnormal oxidative stress, STEAP members are involved in cell transformation and the development of GICs by inhibiting or activating inflammatory process. This review focuses on STEAPs in GICs along with exploring their potential molecular regulatory mechanisms, with an aim to provide a theoretical basis for diagnosis and treatment strategies for patients suffering from these types of cancers.
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Affiliation(s)
- Ze-Xuan Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Wen-Jia Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Zheng Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yan-Yu Hou
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Yang-Zheng Lan
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Hua-Tao Wu
- Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
| | - Jing Liu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong Province, China
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Wang Y, Tang Y, Liu Z, Tan X, Zou Y, Luo S, Yao K. Identification of an inflammation-related risk signature for prognosis and immunotherapeutic response prediction in bladder cancer. Sci Rep 2024; 14:1216. [PMID: 38216619 PMCID: PMC10786915 DOI: 10.1038/s41598-024-51158-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/01/2024] [Indexed: 01/14/2024] Open
Abstract
Tumor inflammation is one of the hallmarks of tumors and is closely related to tumor occurrence and development, providing individualized prognostic prediction. However, few studies have evaluated the relationship between inflammation and the prognosis of bladder urothelial carcinoma (BLCA) patients. Therefore, we constructed a novel inflammation-related prognostic model that included six inflammation-related genes (IRGs) that can precisely predict the survival outcomes of BLCA patients. RNA-seq expression and corresponding clinical data from BLCA patients were downloaded from The Cancer Genome Atlas database. Enrichment analysis was subsequently performed to determine the enrichment of GO terms and KEGG pathways. K‒M analysis was used to compare overall survival (OS). Cox regression and LASSO regression were used to identify prognostic factors and construct the model. Finally, this prognostic model was used to evaluate cell infiltration in the BLCA tumor microenvironment and analyze the effect of immunotherapy in high- and low-risk patients. We established an IRG signature-based prognostic model with 6 IRGs (TNFRSF12A, NR1H3, ITIH4, IL1R1, ELN and CYP26B1), among which TNFRSF12A, IL1R1, ELN and CYP26B1 were unfavorable prognostic factors and NR1H3 and ITIH4 were protective indicators. High-risk score patients in the prognostic model had significantly poorer OS. Additionally, high-risk score patients were associated with an inhibitory immune tumor microenvironment and poor immunotherapy response. We also found a correlation between IRS-related genes and bladder cancer chemotherapy drugs in the drug sensitivity data. The IRG signature-based prognostic model we constructed can predict the prognosis of BLCA patients, providing additional information for individualized prognostic judgment and treatment selection.
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Affiliation(s)
- Yanjun Wang
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Yi Tang
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Zhicheng Liu
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Xingliang Tan
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Yuantao Zou
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Sihao Luo
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China
| | - Kai Yao
- Department of Urology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
- State Key Laboratory of Oncology in Southern China, Guangzhou, 510060, China.
- Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China.
- Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, 510060, China.
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11
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Mehmandar-Oskuie A, Tohidfar M, Hajikhani B, Karimi F. Anticancer effects of cell-free culture supernatant of Escherichia coli in bladder cancer cell line: New insight into the regulation of inflammation. Gene 2023; 889:147795. [PMID: 37708921 DOI: 10.1016/j.gene.2023.147795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 08/23/2023] [Accepted: 09/11/2023] [Indexed: 09/16/2023]
Abstract
Bladder cancer (BC) is the 10th most common malignancy in worldwide, with substantial mortality and morbidity if not treated effectively. According to various research, inflammatory circumstances majorly impact the microenvironment of bladder cancer, and the chronic presence of cytokines and chemokines promotes tumor progression. In this investigation, we explored the impact of cell-free culture supernatant ofEscherichia colistrain 536 on inflammatory cytokines and chemokines in bladder cancer model microarray data (GSE162251). Then we examined in silico outcomes on human bladder cancer cell line 5637 to verify and extrapolate findings. This investigation revealed for the first time that this compound has potent suppressor effects on interleukin 1 beta (IL-1β), C-C motif chemokine ligand 2 (CCL2), and C-X3-C motif chemokine ligand 1 (CX3CL1) gene expression as well as increased NAD(P)H quinone dehydrogenase 1 (NQO1), as an anti-oxidant agent, gene expression in 4, 8, and 24 h. Moreover, we confirmed that c-MYC, a member of the MYC proto-oncogene family, gene expression reduced in 5637 cells in 4 h and then followed up its expression in 8 and 24 h. In addition, our investigation demonstrated that the supernatant raised the BCL2-Associated X Protein/B-cell lymphoma 2 (BAX/BCL2) ratio, and subsequent flow cytometry analysis demonstrated that the supernatant induction apoptosis and necrosis. In conclusion, our findings demonstrate that this compound is a potential candidate for the suppression of bladder cancer progression.
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Affiliation(s)
- Amirreza Mehmandar-Oskuie
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Tohidfar
- Department of Cell & Molecular Biology, Faculty of Life Sciences & Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Bahareh Hajikhani
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Forouzan Karimi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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12
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Wissing MD, O’Flaherty A, Dragomir A, Tanguay S, Kassouf W, Aprikian AG. Chronic prednisone, metformin, and nonsteroidal anti-inflammatory drug use and clinical outcome in a cohort of bladder cancer patients undergoing radical cystectomy in Québec, Canada. BMC Urol 2023; 23:119. [PMID: 37452329 PMCID: PMC10349444 DOI: 10.1186/s12894-023-01287-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Studies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients. METHODS This is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000-2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson's comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone). RESULTS Of 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55-0.82), DSS (HR 0.58, 95%CI 0.45-0.76), and RFS (HR 0.61, 95%CI 0.47-0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07-1.55), DSS (HR 1.38, 95%CI 1.10-1.72), and RFS (HR 1.41, 95%CI 1.13-1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95-1.27), 1.24 (95%CI 1.03-1.48), and 1.22 (95%CI 1.03-1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too. CONCLUSIONS In our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.
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Affiliation(s)
- Michel D. Wissing
- Division of Urology, Department of Surgery, McGill University Health Center – Research Institute, 1001 Boulevard Decarie, D02.8100, Montreal, Québec H4A 3J1 Canada
- Department of Oncology, McGill University, 5100 Maisonneuve Blvd West, Suite 720, Montreal, Québec H4A 3T2 Canada
| | - Ana O’Flaherty
- Division of Urology, Department of Surgery, McGill University Health Center – Research Institute, 1001 Boulevard Decarie, D02.8100, Montreal, Québec H4A 3J1 Canada
| | - Alice Dragomir
- Division of Urology, Department of Surgery, McGill University Health Center – Research Institute, 1001 Boulevard Decarie, D02.8100, Montreal, Québec H4A 3J1 Canada
| | - Simon Tanguay
- Division of Urology, Department of Surgery, McGill University Health Center – Research Institute, 1001 Boulevard Decarie, D02.8100, Montreal, Québec H4A 3J1 Canada
| | - Wassim Kassouf
- Division of Urology, Department of Surgery, McGill University Health Center – Research Institute, 1001 Boulevard Decarie, D02.8100, Montreal, Québec H4A 3J1 Canada
| | - Armen G. Aprikian
- Division of Urology, Department of Surgery, McGill University Health Center – Research Institute, 1001 Boulevard Decarie, D02.8100, Montreal, Québec H4A 3J1 Canada
- Department of Oncology, McGill University, 5100 Maisonneuve Blvd West, Suite 720, Montreal, Québec H4A 3T2 Canada
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13
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Semeniuk-Wojtaś A, Poddębniak-Strama K, Modzelewska M, Baryła M, Dziąg-Dudek E, Syryło T, Górnicka B, Jakieła A, Stec R. Tumour microenvironment as a predictive factor for immunotherapy in non-muscle-invasive bladder cancer. Cancer Immunol Immunother 2023; 72:1971-1989. [PMID: 36928373 PMCID: PMC10264486 DOI: 10.1007/s00262-023-03376-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 01/09/2023] [Indexed: 03/18/2023]
Abstract
Bladder cancer (BC) can be divided into two subgroups depending on invasion of the muscular layer: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Its aggressiveness is associated, inter alia, with genetic aberrations like losses of 1p, 6q, 9p, 9q and 13q; gain of 5p; or alterations in the p53 and p16 pathways. Moreover, there are reported metabolic disturbances connected with poor diagnosis-for example, enhanced aerobic glycolysis, gluconeogenesis or haem catabolism.Currently, the primary way of treatment method is transurethral resection of the bladder tumour (TURBT) with adjuvant Bacillus Calmette-Guérin (BCG) therapy for NMIBC or radical cystectomy for MIBC combined with chemotherapy or immunotherapy. However, intravesical BCG immunotherapy and immune checkpoint inhibitors are not efficient in every case, so appropriate biomarkers are needed in order to select the proper treatment options. It seems that the success of immunotherapy depends mainly on the tumour microenvironment (TME), which reflects the molecular disturbances in the tumour. TME consists of specific conditions like hypoxia or local acidosis and different populations of immune cells including tumour-infiltrating lymphocytes, natural killer cells, neutrophils and B lymphocytes, which are responsible for shaping the response against tumour neoantigens and crucial pathways like the PD-L1/PD-1 axis.In this review, we summarise holistically the impact of the immune system, genetic alterations and metabolic changes that are key factors in immunotherapy success. These findings should enable better understanding of the TME complexity in case of NMIBC and causes of failures of current therapies.
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Affiliation(s)
| | | | | | | | | | - Tomasz Syryło
- Department of General, Active and Oncological Urology, Military Institute of Medicine, Warsaw, Poland
| | - Barbara Górnicka
- Pathomorphology Department, Medical University of Warsaw, Warsaw, Poland
| | - Anna Jakieła
- Oncology Department, 4 Military Clinical Hospital with a Polyclinic, Wroclaw, Poland
| | - Rafał Stec
- Oncology Department, Medical University of Warsaw, Warsaw, Poland
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14
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Abstract
PURPOSE OF THE REVIEW Angiogenesis plays a key role in bladder cancer (BC) pathogenesis. In the last two decades, an increasing number of publications depicting a multitude of novel angiogenic molecules and pathways have emerged. The growing complexity necessitates an evaluation of the breadth of current knowledge to highlight key findings and guide future research. RECENT FINDINGS Angiogenesis is a dynamic biologic process that is inherently difficult to assess. Clinical assessment of angiogenesis in BCs is advancing with the integration of image analysis systems and dynamic contrast-enhanced and magnetic resonance imaging (DCE-MRI). Tumour-associated macrophages (TAMs) significantly influence the angiogenic process, and further research is needed to assess their potential as therapeutic targets. A rapidly growing list of non-coding RNAs affect angiogenesis in BCs, partly through modulation of vascular endothelial growth factor (VEGF) activity. Vascular mimicry (VM) has been repeatedly associated with increased tumour aggressiveness in BCs. Standardised assays are needed for appropriate identification and quantification of VM channels. This article demonstrates the dynamic and complex nature of the angiogenic process and asserts the need for further studies to deepen our understanding.
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Affiliation(s)
- Ghada Elayat
- Department of Natural Science, Middlesex University, London, UK
- Department of Histopathology, Tanta University, Tanta, Egypt
| | - Ivan Punev
- Department of Natural Science, Middlesex University, London, UK
| | - Abdel Selim
- Histopathology Department, King’s Health Partners, King’s College Hospital, London, UK
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15
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Blood-Based Biomarkers as Prognostic Factors of Recurrent Disease after Radical Cystectomy: A Systematic Review and Meta-Analysis. Int J Mol Sci 2023; 24:ijms24065846. [PMID: 36982918 PMCID: PMC10056816 DOI: 10.3390/ijms24065846] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/22/2023] Open
Abstract
Survival outcomes after radical cystectomy (RC) for bladder cancer (BCa) have not improved in recent decades; nevertheless, RC remains the standard treatment for patients with localized muscle-invasive BCa. Identification of the patients most likely to benefit from RC only versus a combination with systemic therapy versus systemic therapy first/only and bladder-sparing is needed. This systematic review and meta-analysis pools the data from published studies on blood-based biomarkers to help prognosticate disease recurrence after RC. A literature search on PubMed and Scopus was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Articles published before November 2022 were screened for eligibility. A meta-analysis was performed on studies investigating the association of the neutrophil-to-lymphocyte ratio (NLR), the only biomarker with sufficient data, with recurrence-free survival. The systematic review identified 33 studies, and 7 articles were included in the meta-analysis. Our results demonstrated a statistically significant correlation between elevated NLR and an increased risk of disease recurrence (HR 1.26; 95% CI 1.09, 1.45; p = 0.002) after RC. The systematic review identified various other inflammatory biomarkers, such as interleukin-6 or the albumin-to-globulin ratio, which have been reported to have a prognostic impact on recurrence after RC. Besides that, the nutritional status, factors of angiogenesis and circulating tumor cells, and DNA seem to be promising tools for the prognostication of recurrence after RC. Due to the high heterogeneity between the studies and the different cut-off values of biomarkers, prospective and validation trials with larger sample sizes and standardized cut-off values should be conducted to strengthen the approach in using biomarkers as a tool for risk stratification in clinical decision-making for patients with localized muscle-invasive BCa.
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16
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The Urinary Microbiome and Bladder Cancer. Life (Basel) 2023; 13:life13030812. [PMID: 36983967 PMCID: PMC10053959 DOI: 10.3390/life13030812] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/09/2023] [Accepted: 03/11/2023] [Indexed: 03/19/2023] Open
Abstract
Bladder cancer is the 10th most common cancer worldwide. Approximately 75% of patients with bladder cancer will present with non-muscle invasive disease. Patients are usually treated with transurethral resection of bladder tumor (TURBT), in addition to adjuvant intravesical therapy (chemotherapy or anti-cancer immunotherapy with Bacillus Calmette Guerin- BCG) for those at intermediate-risk and high-risk of recurrence and progression. For many years, urine has been thought to be “sterile”; however, advanced microbiological and molecular techniques, including 16S ribosomal RNA (16S rRNA) sequencing, have negated that previous paradigm and confirmed the presence of a urinary microbiome. The urinary microbiome has been associated with several urological diseases, including interstitial cystitis, urgency urinary incontinence, neurogenic bladder dysfunction, and others. More recently, many reports are emerging about the role of the urinary microbiome in urothelial carcinogenesis, including gender disparity in bladder cancer and responses to treatments. The urinary microbiome may serve as a biomarker that can help with risk stratification as well as prediction of the response to intravesical therapies. However, the microbiome literature has been hampered by the lack of a unified standardized methodology for sample collection, type, preservation, processing, as well as bioinformatics analysis. Herein we describe and critique the literature on the association between urinary microbiome and bladder cancer and highlight some of the future directions.
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17
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Teng C, Zheng S, Wan W, Liu L, Yu S, Cao M, Lu W, Shan Y. Fatty foods and the risk of bladder cancer: A case-control study. Nutrition 2023; 106:111868. [PMID: 36411185 DOI: 10.1016/j.nut.2022.111868] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 09/21/2022] [Accepted: 10/06/2022] [Indexed: 11/21/2022]
Abstract
OBJECTIVE The aim of this study was to explore the association between dietary fatty foods and the risk for bladder cancer. METHODS Patients newly diagnosed with bladder cancer (n = 113) and 292 controls were recruited. A food frequency questionnaire (FFQ) was used to investigate the food intake within 1 y. Multivariate logistic regression model was used to estimated odds ratio (OR) between different types of fatty food consumption and bladder cancer. RESULTS The consumption of soybean oil, the largest proportion of cooking oil, in both groups were much higher than the Chinese recommended dietary intake, especially in the control group. Higher intake of red meat was also observed in bladder cancer cases, although lower intakes of marine fish, egg, milk, and dairy products and nuts were observed in controls. After adjusting for potential confounders, the intakes of marine fish and milk and dairy products were negatively correlated with bladder cancer, with the adjusted OR of 0.28 (95% confidence interval [CI], 0.15-0.55) and 0.36 (95% CI, 0.19-0.69). Total nuts were related to a 76% reduction in bladder cancer risk (OR, 0.24; 95% CI, 0.12-0.48). There was clear and positive association between soybean oil and bladder cancer risk with OR of 3.47 (95 % CI, 1.69-7.14). In stratified analyses by sex and smoking status, the relationship was similar for most results, except for milk and dairy products. The negative correlation between milk and dairy products and bladder cancer risk was only found in men; and milk and dairy products and bladder cancer risk were irrelevant by smoking status. No significant association was found between the intakes of other foods and bladder cancer risk. CONCLUSIONS Intake of nuts and marine fish may be beneficial for the prevention of bladder cancer. The protective effect of milk and dairy products was only found in men with bladder cancer. High soybean oil intake was a risk factor for bladder cancer.
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Affiliation(s)
- Chunying Teng
- Department of Food Science and Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, China; School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Sicong Zheng
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Wenting Wan
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Lihua Liu
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Siwen Yu
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Muyang Cao
- Department of Urology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Weihong Lu
- Department of Food Science and Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, China.
| | - Yujuan Shan
- School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
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18
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Lu C, Gao S, Zhang L, Shi X, Chen Y, Wei S, Zuo L, Zhang L. Nuclear Protein 1 Expression Is Associated with PPARG in Bladder Transitional Cell Carcinoma. PPAR Res 2023; 2023:6797694. [PMID: 37197716 PMCID: PMC10185424 DOI: 10.1155/2023/6797694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 03/20/2023] [Accepted: 04/20/2023] [Indexed: 05/19/2023] Open
Abstract
Background The Nuclear protein 1 gene was first discovered in acute pancreatitis and functions as an oncogene in cancer progression and drug resistance. However, the role of Nuclear protein 1 in bladder transitional cell carcinoma (BTCC) is still unclear. Methods The Cancer Genome Atlas database and immunohistochemical analysis were adopted to evaluate Nuclear protein 1 expression in BTCC. We applied lentivirus-mediated small-interfering RNA to down-regulate the expression of Nuclear protein 1 in BTCC cell lines. We further performed an Affymetrix microarray and Gene Set Enrichment Analysis (GSEA) to assess the genes and signaling pathways related to Nuclear protein 1. Results We found that Nuclear protein 1 expression was up-regulated in BTCC and positively related to the degree of BTCC malignancy. Compared with Caucasian patients with BTCC, Nuclear protein 1 expression was attenuated in Asian patients. The Affymetrix microarray showed that lipopolysaccharide was the upstream regulatory factor of Nuclear protein 1 in BTCC. The GSEA indicated that Nuclear protein 1 expression was associated with signaling pathways in cancer, peroxisome proliferator-activated receptor (PPAR) pathways, and RNA degradation. The expression of Nuclear protein 1 was negatively correlated with PPARG (R = -0.290, P < 0.001), but not with PPARA (R = 0.047, P = 0.344) and PPARD (R = -0.055, P = 0.260). Conclusions The study findings indicate that Nuclear protein 1 is positively associated with the malignancy degree of BTCC and that Nuclear protein 1 expression is negatively correlated with PPARG.
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Affiliation(s)
- Chao Lu
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Shenglin Gao
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Li Zhang
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Xiaokai Shi
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Yin Chen
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Shuzhang Wei
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Li Zuo
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
| | - Lifeng Zhang
- Department of Urology, Changzhou Second People's Hospital, 29 Xinglong Road, Changzhou 213003, China
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19
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Maynard JP, Sfanos KS. P2 purinergic receptor dysregulation in urologic disease. Purinergic Signal 2022; 18:267-287. [PMID: 35687210 PMCID: PMC9184359 DOI: 10.1007/s11302-022-09875-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/25/2022] [Indexed: 11/25/2022] Open
Abstract
P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides. Dysregulation of these receptors is common in pathological states and often associated with disease initiation, progression, or aggressiveness. Indeed, P2 purinergic receptor expression is altered across multiple urologic disorders including chronic kidney disease, polycystic kidney disease, interstitial cystitis, urinary incontinence, overactive bladder syndrome, prostatitis, and benign prostatic hyperplasia. P2 purinergic receptors are likewise indirectly associated with these disorders via receptor-mediated inflammation and pain, a common characteristic across most urologic disorders. Furthermore, select P2 purinergic receptors are overexpressed in urologic cancer including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma, and pre-clinical studies depict P2 purinergic receptors as potential therapeutic targets. Herein, we highlight the compelling evidence for the exploration of P2 purinergic receptors as biomarkers and therapeutic targets in urologic cancers and other urologic disease. Likewise, there is currently optimism for P2 purinergic receptor-targeted therapeutics for the treatment of inflammation and pain associated with urologic diseases. Further exploration of the common pathways linking P2 purinergic receptor dysregulation to urologic disease might ultimately help in gaining new mechanistic insight into disease processes and therapeutic targeting.
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Affiliation(s)
- Janielle P Maynard
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. .,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.
| | - Karen S Sfanos
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.,Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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20
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Kaur J, Bhardwaj A, Wuest F. Fluorine-18 Labelled Radioligands for PET Imaging of Cyclooxygenase-2. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123722. [PMID: 35744851 PMCID: PMC9227202 DOI: 10.3390/molecules27123722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 11/18/2022]
Abstract
Molecular imaging probes enable the early and accurate detection of disease-specific biomarkers and facilitate personalized treatment of many chronic diseases, including cancer. Among current clinically used functional imaging modalities, positron emission tomography (PET) plays a significant role in cancer detection and in monitoring the response to therapeutic interventions. Several preclinical and clinical studies have demonstrated the crucial involvement of cyclooxygenase-2 (COX-2) isozyme in cancer development and progression, making COX-2 a promising cancer biomarker. A variety of COX-2-targeting PET radioligands has been developed based on anti-inflammatory drugs and selective COX-2 inhibitors. However, many of those suffer from non-specific binding and insufficient metabolic stability. This article highlights examples of COX-2-targeting PET radioligands labelled with the short-lived positron emitter 18F, including radiosynthesis and PET imaging studies published in the last decade (2012–2021).
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Affiliation(s)
- Jatinder Kaur
- Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada;
- Correspondence: (J.K.); (F.W.)
| | - Atul Bhardwaj
- Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada;
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 1Z2, Canada
| | - Frank Wuest
- Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada;
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 1Z2, Canada
- Department of Chemistry, University of Alberta, Edmonton, AB T6G 1Z2, Canada
- Correspondence: (J.K.); (F.W.)
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21
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Alnajar H, Ravichandran H, Figueiredo Rendeiro A, Ohara K, Al Zoughbi W, Manohar J, Greco N, Sigouros M, Fox J, Muth E, Angiuoli S, Faltas B, Shusterman M, Sternberg CN, Elemento O, Mosquera JM. Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab. Cold Spring Harb Mol Case Stud 2022; 8:mcs.a006151. [PMID: 35483877 PMCID: PMC9059779 DOI: 10.1101/mcs.a006151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 03/03/2022] [Indexed: 11/30/2022] Open
Abstract
Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios. The need for reliable biomarkers for treatment stratification is still under research. Here, we present a novel case report of the first Imaging Mass Cytometry (IMC) analysis done in SUC to investigate the immune cell repertoire and PD-L1 expression in a patient who presented with metastatic SUC and experienced a prolonged response to the anti-PD1 immune checkpoint inhibitor pembrolizumab after progression on first-line chemotherapy. This case report provides an important platform for translating these findings to a larger cohort of UC and UC variants.
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Affiliation(s)
- Hussein Alnajar
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, 10021, USA
| | - Hiranmayi Ravichandran
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA;,Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, 10021, USA
| | - André Figueiredo Rendeiro
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA;,Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, 10021, USA
| | - Kentaro Ohara
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, 10021, USA;,Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA
| | - Wael Al Zoughbi
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, 10021, USA;,Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA
| | - Jyothi Manohar
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA
| | - Noah Greco
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA
| | - Michael Sigouros
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA
| | - Jesse Fox
- Personal Genome Diagnostics, Inc., Baltimore, Maryland 21224, USA
| | - Emily Muth
- Personal Genome Diagnostics, Inc., Baltimore, Maryland 21224, USA
| | - Samuel Angiuoli
- Personal Genome Diagnostics, Inc., Baltimore, Maryland 21224, USA
| | - Bishoy Faltas
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA;,Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, New York 10021, USA
| | - Michael Shusterman
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, New York 10021, USA
| | - Cora N. Sternberg
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA;,Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, New York 10021, USA
| | - Olivier Elemento
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA;,Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, 10021, USA;,Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, 10021, USA
| | - Juan Miguel Mosquera
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, 10021, USA;,Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and NewYork-Presbyterian, New York, New York 10021, USA
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22
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Xiong S, Huang W, Liu X, Chen Q, Ding Y, Huang H, Zhang R, Guo J. Celecoxib Synergistically Enhances MLN4924-Induced Cytotoxicity and EMT Inhibition Via AKT and ERK Pathways in Human Urothelial Carcinoma. Cell Transplant 2022; 31:9636897221077921. [PMID: 35176901 PMCID: PMC8859662 DOI: 10.1177/09636897221077921] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
MLN4924 is a specific small-molecule inhibitor of NEDD8-activating enzyme (NAE) that blocks the neddylation modification cascade. Several I/II/III clinical trials suggested that MLN4924 exerts an antitumor effect against various malignancies. However, recent studies have also found that MLN4924 activates the PI3K/AKT and MAPK/ERK signal pathways, important regulators of tumorigenesis, and drug resistance in human urothelial carcinoma (UC). This study examined the synergistic effect of celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, on MLN4924-induced cytotoxicity and epithelial-mesenchymal transition (EMT) inhibition via AKT and ERK pathways in human UC. We performed both in vitro and in vivo experiments. Briefly, a combination of MLN4924 and celecoxib reduced the protein expression of p-AKT(S473) and p-ERK in UC cell lines. Moreover, celecoxib shifted the half-maximal inhibitory concentration (IC50) curve of MLN4924 to the left, and the combinational effect of MLN4924 and celecoxib showed significant synergism in T24 and 5637 cells. Also, celecoxib enhanced the MLN4924 antitumor effects of inhibiting UC cell growth, colony formation, migration, invasion, and inducing apoptosis. In addition, celecoxib potentiated the MLN4924-induced EMT, decreased the expression of N-cadherin and vimentin, and activated the expression of E-cadherin. Celecoxib also increased the expression of pro-apoptosis proteins PARP and BAX and reduced the expression of antiapoptosis protein Bcl2. In vivo study indicated that the combination of MLN4924 and celecoxib synergistically suppressed the tumor growth in a UC xenograft nude-mice model, which was further supported by immunohistochemistry of tumor tissues. To sum up, our study revealed that celecoxib synergistically enhanced MLN4924-induced cytotoxicity and EMT inhibition in UC. It also inhibited the activation of AKT and ERK pathways, which were activated by MLN4924. These discoveries provide a new drug combination strategy for UC treatment.
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Affiliation(s)
- Shida Xiong
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Wei Huang
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Xiaoqiang Liu
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Qian Chen
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Yi Ding
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Haoxuan Huang
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Ru Zhang
- Department of Urology, Yichun Second People's Hospital, Yichun, P.R. China
| | - Ju Guo
- Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
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23
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Huang X, Pan T, Yan L, Jin T, Zhang R, Chen B, Feng J, Duan T, Xiang Y, Zhang M, Chen X, Yang Z, Zhang W, Ding X, Xie T, Sui X. The inflammatory microenvironment and the urinary microbiome in the initiation and progression of bladder cancer. Genes Dis 2021; 8:781-797. [PMID: 34522708 PMCID: PMC8427242 DOI: 10.1016/j.gendis.2020.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
Accumulating evidence suggests that chronic inflammation may play a critical role in various malignancies, including bladder cancer. This hypothesis stems in part from inflammatory cells observed in the urethral microenvironment. Chronic inflammation may drive neoplastic transformation and the progression of bladder cancer by activating a series of inflammatory molecules and signals. Recently, it has been shown that the microbiome also plays an important role in the development and progression of bladder cancer, which can be mediated through the stimulation of chronic inflammation. In effect, the urinary microbiome can play a role in establishing the inflammatory urethral microenvironment that may facilitate the development and progression of bladder cancer. In other words, chronic inflammation caused by the urinary microbiome may promote the initiation and progression of bladder cancer. Here, we provide a detailed and comprehensive account of the link between chronic inflammation, the microbiome and bladder cancer. Finally, we highlight that targeting the urinary microbiome might enable the development of strategies for bladder cancer prevention and personalized treatment.
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Affiliation(s)
- Xingxing Huang
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Ting Pan
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Lili Yan
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Ting Jin
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Ruonan Zhang
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Bi Chen
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Jiao Feng
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Ting Duan
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Yu Xiang
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Mingming Zhang
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Xiaying Chen
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Zuyi Yang
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Wenzheng Zhang
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, PR China
| | - Tian Xie
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
| | - Xinbing Sui
- Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, College of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 310015, PR China
- College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang Province, 311121, PR China
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, PR China
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24
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Yuan S, Fang C, Leng WD, Wu L, Li BH, Wang XH, Hu H, Zeng XT. Oral microbiota in the oral-genitourinary axis: identifying periodontitis as a potential risk of genitourinary cancers. Mil Med Res 2021; 8:54. [PMID: 34588004 PMCID: PMC8480014 DOI: 10.1186/s40779-021-00344-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
Periodontitis has been proposed as a novel risk factor of genitourinary cancers: although periodontitis and genitourinary cancers are two totally distinct types of disorders, epidemiological and clinical studies, have established associations between them. Dysbiosis of oral microbiota has already been established as a major factor contributing to periodontitis. Recent emerging epidemiological evidence and the detection of oral microbiota in genitourinary organs indicate the presence of an oral-genitourinary axis and oral microbiota may be involved in the pathogenesis of genitourinary cancers. Therefore, oral microbiota provides the bridge between periodontitis and genitourinary cancers. We have carried out this narrative review which summarizes epidemiological studies exploring the association between periodontitis and genitourinary cancers. We have also highlighted the current evidence demonstrating the capacity of oral microbiota to regulate almost all hallmarks of cancer, and proposed the potential mechanisms of oral microbiota in the development of genitourinary cancers.
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Affiliation(s)
- Shuai Yuan
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
| | - Cheng Fang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
| | - Wei-Dong Leng
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000 Hubei China
| | - Lan Wu
- Department of Stomatology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
| | - Bing-Hui Li
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
| | - Xing-Huan Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
| | - Hailiang Hu
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710 USA
- School of Medicine, Southern University of Science and Technology, Shenzhen, 518055 China
| | - Xian-Tao Zeng
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei China
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25
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Jung J, Liao H, Coker SA, Liang H, Hancock JF, Denicourt C, Venkatachalam K. p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1. iScience 2021; 24:102701. [PMID: 34222845 PMCID: PMC8243020 DOI: 10.1016/j.isci.2021.102701] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 03/10/2021] [Accepted: 06/07/2021] [Indexed: 12/13/2022] Open
Abstract
Inhibition of TRPML1, which is encoded by MCOLN1, is known to deter cell proliferation in various malignancies. Here, we report that the tumor suppressor, p53, represses MCOLN1 in the urothelium such that either the constitutive loss or ectopic knockdown of TP53-in both healthy and bladder cancer cells-increased MCOLN1 expression. Conversely, nutlin-mediated activation of p53 led to the repression of MCOLN1. Elevated MCOLN1 expression in p53-deficient cancer cells, though not sufficient for bolstering proliferation, augmented the effects of oncogenic HRAS on proliferation, cytokine production, and invasion. Our data suggest that owing to derepression of MCOLN1, urothelial cells lacking p53 are poised for tumorigenesis driven by oncogenic HRAS. Given our prior findings that HRAS mutations predict addiction to TRPML1, this study points to the utility of TRPML1 inhibitors for mitigating the growth of a subset of urothelial tumors that lack p53.
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Affiliation(s)
- Jewon Jung
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
| | - Han Liao
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
| | - Shannon A. Coker
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
| | - Hong Liang
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
| | - John F. Hancock
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
- Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center and UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Catherine Denicourt
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
- Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center and UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Kartik Venkatachalam
- Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center (UTHealth), Houston, TX 77030, USA
- Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center and UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
- Graduate Program in Neuroscience, MD Anderson Cancer Center and UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
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26
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Caviglia GP, Martini G, Armandi A, Rosso C, Vernero M, Bugianesi E, Astegiano M, Saracco GM, Ribaldone DG. Risk Factors of Urothelial Cancer in Inflammatory Bowel Disease. J Clin Med 2021; 10:3257. [PMID: 34362041 PMCID: PMC8347965 DOI: 10.3390/jcm10153257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/22/2021] [Accepted: 07/22/2021] [Indexed: 01/31/2023] Open
Abstract
Extraintestinal cancers are important complications in patients with inflammatory bowel disease (IBD). A limited number of publications are available regarding the association between IBD and urothelial cancer. The primary outcome of our study was the comparison of the prevalence of urothelial cancer in patients with IBD with respect to the prevalence in the general population. Secondary outcomes were the assessment of risk factors for the onset of urothelial cancer in IBD. In a retrospective study we examined the medical records of all patients with a confirmed diagnosis of IBD followed in our clinic between 1978 and 2021. For each of the patients with identified urothelial cancer, more than ten patients without cancer were analyzed. Furthermore, 5739 patients with IBD were analyzed and 24 patients diagnosed with urothelial cancer were identified. The incidence of urothelial cancer, compared with the incidence in the general population, was not significantly different (0.42% vs. 0.42%; p = 0.98). Twenty-three cases were then compared (1 case was discarded due to lack of follow-up data) against 250 controls. During the multivariate analysis, smoking (odds ratio, OR = 8.15; 95% confidence interval, CI = 1.76-37.63; p = 0.007) and male sex (OR = 4.04; 95% CI = 1.29-12.66; p = 0.016) were found as risk factors. In conclusion, patients with IBD have a similar risk of developing urothelial cancer compared to the general population, but males with a history of smoking are at increased risk.
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Affiliation(s)
- Gian Paolo Caviglia
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
| | - Giorgio Martini
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
| | - Angelo Armandi
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
| | - Chiara Rosso
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
| | - Marta Vernero
- Department of Internal Medicine, San Matteo Hospital, 27100 Pavia, Italy;
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
| | - Marco Astegiano
- Department of General and Specialist Medicine, Gastroenterologia-U, Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy;
| | - Giorgio Maria Saracco
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
| | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Torino, Italy; (G.P.C.); (G.M.); (C.R.); (E.B.); (G.M.S.)
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27
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Gómez-Valenzuela F, Escobar E, Pérez-Tomás R, Montecinos VP. The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition. Front Oncol 2021; 11:686792. [PMID: 34178680 PMCID: PMC8222670 DOI: 10.3389/fonc.2021.686792] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
The tumor microenvironment (TME) corresponds to a complex and dynamic interconnection between the extracellular matrix and malignant cells and their surrounding stroma composed of immune and mesenchymal cells. The TME has constant cellular communication through cytokines that sustain an inflammatory profile, which favors tumor progression, angiogenesis, cell invasion, and metastasis. Although the epithelial-mesenchymal transition (EMT) represents a relevant metastasis-initiating event that promotes an invasive phenotype in malignant epithelial cells, its relationship with the inflammatory profile of the TME is poorly understood. Previous evidence strongly suggests that cyclooxygenase-2 (COX-2) overexpression, a pro-inflammatory enzyme related to chronic unresolved inflammation, is associated with common EMT-signaling pathways. This review article summarizes how COX-2 overexpression, within the context of the TME, orchestrates the EMT process and promotes initial metastatic-related events.
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Affiliation(s)
- Fernán Gómez-Valenzuela
- Department of Hematology-Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Enrico Escobar
- Department of Oral Pathology and Medicine, Faculty of Dentistry, University of Chile, Santiago, Chile
| | - Ricardo Pérez-Tomás
- Department of Pathology and Experimental Therapy - Bellvitge, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Viviana P Montecinos
- Department of Hematology-Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile
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28
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Ackerman RS, Luddy KA, Icard BE, Piñeiro Fernández J, Gatenby RA, Muncey AR. The Effects of Anesthetics and Perioperative Medications on Immune Function: A Narrative Review. Anesth Analg 2021; 133:676-689. [PMID: 34100781 DOI: 10.1213/ane.0000000000005607] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Preclinical and clinical studies have sought to better understand the effect of anesthetic agents, both volatile and intravenous, and perioperative adjuvant medications on immune function. The immune system has evolved to incorporate both innate and adaptive components, which are delicately interwoven and essential for host defense from pathogens and malignancy. This review summarizes the complex and nuanced relationship that exists between each anesthetic agent or perioperative adjuvant medication studied and innate and adaptive immune function with resultant clinical implications. The most commonly used anesthetic agents were chosen for review including volatile agents (sevoflurane, isoflurane, desflurane, and halothane), intravenous agents (propofol, ketamine, etomidate, and dexmedetomidine), and perioperative adjuvant medications (benzodiazepines, opioids, nonsteroidal anti-inflammatory drugs [NSAIDs], and local anesthetic agents). Patients who undergo surgery experience varying combinations of the aforementioned anesthetic agents and adjuncts, depending on the type of surgery and their comorbidities. Each has unique effects on immunity, which may be more or less ideal depending on the clinical situation. Further study is needed to better understand the clinical effects of these relationships so that patient-specific strategies can be developed to improve surgical outcomes.
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Affiliation(s)
- Robert S Ackerman
- From the Department of Anesthesiology, University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - Benjamin E Icard
- University of South Florida Morsani College of Medicine, Tampa, Florida
| | | | - Robert A Gatenby
- the Department of Cancer Biology and Evolution.,Department of Radiology
| | - Aaron R Muncey
- Department of Anesthesiology, H. Lee Moffitt Cancer Center, Tampa, Florida
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29
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Rs-10889677 variant in interleukin-23 receptor may contribute to creating an inflammatory milieu more susceptible to bladder tumourigenesis: report and meta-analysis. Immunogenetics 2021; 73:207-226. [PMID: 33665735 DOI: 10.1007/s00251-021-01205-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/20/2021] [Indexed: 12/20/2022]
Abstract
Bladder cancer (BLC) is a recurrent high-risk malignancy typified by an inherent localised chronic inflammation. IL-23-receptor (IL-23R), as a positive regulator in the priming of T helper-17 cells, is regarded a principal coordinator of inflammation-propelled neoplasia. In this article, we indented firstly to scrutinise the influence of rs10889677"A/C" SNP located in IL-23R-gene on BLC development and progression among Egyptians. Findings revealed that the rs10889677"C" allele was significantly associated with the increased BLC risk and its higher frequencies were plainly noticeable in high-grade and invasive tumours when applied the dominant/homozygous/allelic genetic models. Under the same genetic models, elevated serum levels of IL-23R protein in BLC patients were pertinently correlated with the rs10889677"A/C" polymorphism. As a corollary, the frequent up-regulation of IL-23R exerts a subsequent activation of the IL-23/17 inflammatory axis. That is experienced as a drastic increase in IL-23 and IL17 levels under the dominant/homozygous/heterozygous/recessive models. Second, study further described how the rs10889677 variant confers its pro-tumoural influences on IL-23R-bearing immune cells, involving tumour-associated macrophages (TAMs), natural killers (NKs) and CD4+ T-helper cells. When the dominant model was adopted, it was observed that patients bearing the rs10889677 "C" allele had lower counts of IL-23R-positive CD56+NKs and CD4+ T-cells, in tandem with higher levels of IL-23R-positive CD14+ TAMs compared with those with rs10889677 "A" allele. To entrench the idea, we did a meta-analysis on BLC patients from three different ethnicities (Asian, Caucasians and African). We observed that rs10889677"SNP" is significantly correlated with increased risk of BLCs in the overall population using over-dominant model. Consequently, authors suggested that the rs10889677 variant could be directly implicated in developing inflammatory environment more prone to generating malignancy.
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Zhang C, Liu S, Peng L, Wu J, Zeng X, Lu Y, Shen H, Luo D. Does inflammatory bowel disease increase the risk of lower urinary tract tumors: a meta-analysis. Transl Androl Urol 2021; 10:164-173. [PMID: 33532306 PMCID: PMC7844520 DOI: 10.21037/tau-20-1020] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is characterized by chronic inflammation that could be a risk factor for extraintestinal cancer. The aim of this study is to evaluate whether inflammatory bowel disease is related to the risk of lower urinary tract tumors. Methods A systematical research was performed on various medical databases including PubMed, the Cochrane Library, Embase and Web of Science from inception to April 2020. Data were independently extracted by two reviewers. The Newcastle-Ottawa Scale and the Oxford Centre for Evidence-Based Medicine criteria were used to assess the quality of included articles. The analysis was completed by STATA version 14.2. Results Six hundred and twelve of records were initially identified and 16 studies were included in the final analysis. In general, inflammatory bowel disease patients were not at increased risk of prostate cancer, bladder cancer and male genital cancer. In the subgroup analysis, Crohn’s disease patients seemed to have borderline increased risk of prostate cancer [standardized incidence ratio: 1.05; 95% confidence interval (CI): 0.90–1.21; I2=15.1%] and bladder cancer (standardized incidence ratio: 1.19; 95% CI: 0.94–1.44; I2=0.0%), and ulcerative colitis patients seemed to have borderline increased risk of prostate cancer (standardized incidence ratio: 1.13; 95% CI: 0.93–1.33; I2=73.5%). Conclusions Inflammatory bowel disease did not significantly increase the risk of prostate cancer, bladder cancer and male genital cancer. Crohn’s disease patients seemed to have a higher risk of prostate cancer and bladder cancer, and ulcerative colitis patients seemed to have a higher risk of prostate cancer. ulcerative colitis patients in East Asian countries have significantly increased prostate cancer risk.
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Affiliation(s)
- Chi Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Shengzhuo Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Liao Peng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Jiapei Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao Zeng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yiping Lu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Shen
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Deyi Luo
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
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Bi H, Yan Y, Wang D, Qin Z, Wang G, Ma L, Huang Y, Lu J. Predictive value of preoperative lymphocyte-to-monocyte ratio on survival outcomes in bladder cancer patients after radical cystectomy. J Cancer 2021; 12:305-315. [PMID: 33391427 PMCID: PMC7738993 DOI: 10.7150/jca.50603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 10/25/2020] [Indexed: 12/26/2022] Open
Abstract
Purpose: To determine the prognostic significance of the pre-operative lymphocyte-to-monocyte (LMR) in patients with bladder cancer (BCa) who underwent radical cystectomy (RC), and to assess its prognostic benefit compared to models relying solely on clinicopathological factors. Materials and Methods: A retrospective analysis of the 342 BCa patients undergoing RC at our institution from 2004 to 2017 was conducted to assess LMR prognostic significance. Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan-Meier method. Cox regression models identified risk factors for survival outcomes. Two new models were developed based on basal models to predict OS and CSS at 1, 3, and 5 years after RC. The accuracy of the new models was evaluated using receiver operating characteristic curves as well as the concordance index. We also conducted decision curve analysis (DCA) to assess their net benefit. Results: An association between excellent long-term patient survival outcomes and higher LMR levels was observed. The median OS and CSS for higher LMR level in patients was 98.8 months and >120 months, respectively. Cox regression multivariate analysis showed that pre-operative LMR, as a continuous variable, was an independent survival outcome predictor (p<0.001). The utilization of LMR in the standard model resulted in significant discriminatory improvement in OS (5.6%, p<0.001) and CSS (4.9%, p=0.001) prediction. Moreover, as shown in DCA, utilization of the new model, including LMR, resulted in a net benefit compared to base models for predicting OS and CSS at 1, 3, and 5 years. Conclusions: An independent association was observed between higher pre-operative LMR in BCa patients undergoing RC and significantly better OS and CSS. In addition, a significant improvement in predictive accuracy was observed with LMR inclusion in multiparametric prediction tools. Therefore, LMR may be utilized in pre-operative patient risk stratification to assist in patient counseling and clinical decision making.
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Affiliation(s)
- Hai Bi
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Ye Yan
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Dong Wang
- Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, PR China
| | - Zijian Qin
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Guoliang Wang
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Lulin Ma
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Yi Huang
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
| | - Jian Lu
- Department of Urology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100191, PR China
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Yu EYW, Wesselius A, Mehrkanoon S, Brinkman M, van den Brandt P, White E, Weiderpass E, Le Calvez-Kelm F, Gunter M, Huybrechts I, Liedberg F, Skeie G, Tjonneland A, Riboli E, Giles GG, Milne RL, Zeegers MP. Grain and dietary fiber intake and bladder cancer risk: a pooled analysis of prospective cohort studies. Am J Clin Nutr 2020; 112:1252-1266. [PMID: 32778880 PMCID: PMC7657329 DOI: 10.1093/ajcn/nqaa215] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 07/08/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer. OBJECTIVES Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber. METHODS We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose-response relations were examined using fractional polynomial regression models. RESULTS We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose-response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism. CONCLUSIONS Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings.
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Affiliation(s)
- Evan Y W Yu
- Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Anke Wesselius
- Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Siamak Mehrkanoon
- Department of Data Science and Knowledge Engineering, Maastricht University, Maastricht, Netherlands
| | - Maree Brinkman
- Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
- Department of Clinical Studies and Nutritional Epidemiology, Nutrition Biomed Research Institute, Melbourne, Victoria, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
| | - Piet van den Brandt
- Department of Epidemiology, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
- Department of Epidemiology, School for Public Health and Primary Care, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Emily White
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | | | - Marc Gunter
- International Agency for Research on Cancer/WHO, Lyon, France
| | - Inge Huybrechts
- International Agency for Research on Cancer/WHO, Lyon, France
| | - Fredrik Liedberg
- Department of Urology, Skåne University Hospital, Malmö, Sweden
- Institution of Translational Medicine, Lund University, Malmö, Sweden
| | - Guri Skeie
- Department of Community Medicine, UIT The Arctic University of Norway, Tromsø, Norway
| | - Anne Tjonneland
- Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Maurice P Zeegers
- Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
- CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, Netherlands
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
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Jiao F, Sun H, Yang Q, Sun H, Wang Z, Liu M, Chen J. Identification of FADS1 Through Common Gene Expression Profiles for Predicting Survival in Patients with Bladder Cancer. Cancer Manag Res 2020; 12:8325-8339. [PMID: 32982427 PMCID: PMC7489952 DOI: 10.2147/cmar.s254316] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/05/2020] [Indexed: 12/24/2022] Open
Abstract
Purpose Aim of this study was to identify biomarkers between different grades of bladder cancer (BLCA) and its prognostic value. Methods mRNA expression data from GSE32549 and GSE71576 were extracted for further analysis. Differentially expressed genes (DEGs) were identified using GEO2R web tool. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein–protein interaction (PPI) network were conducted to explore the function and relationship of DEGs. The Cancer Genome Atlas (TCGA) database was used for external validation and Gene set enrichment analysis (GSEA) analysis was used to further identify FADS1 pathways. Bladder cancer cells and patient specimens were used to further demonstrate the function of FADS1. Results Datasets from GEO identified a panel of DEGs. Functional enrichment analysis highlighted that DEGs were associated with nuclear division, spindle, cell cycle and p53 signaling pathway. External validation from TCGA demonstrated that FADS1 was an independent prognostic marker in BLCA patients. In cell lines and tumor specimen analysis, FADS1 was overexpressed in the tumor specimen, compared with adjacent tissues, and positively correlated with tumor grade of BLCA. Moreover, FADS1 could enhance the proliferation ability and influence cell cycle of bladder cancer cells. Conclusion FADS1 was an independent prognostic biomarker for BLCA and could confer the bladder cancer cells increased proliferation ability.
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Affiliation(s)
- Fangdong Jiao
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
| | - Hao Sun
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
| | - Qingya Yang
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
| | - Hui Sun
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
| | - Zehua Wang
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
| | - Ming Liu
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
| | - Jun Chen
- Department of Urology, Shandong University Qilu Hospital (Qingdao), Qingdao, People's Republic of China
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Belgorosky D, Girouard J, Langle YV, Hamelin-Morrissete J, Marino L, Agüero EI, Malagrino H, Reyes-Moreno C, Eiján AM. Relevance of iNOS expression in tumor growth and maintenance of cancer stem cells in a bladder cancer model. J Mol Med (Berl) 2020; 98:1615-1627. [PMID: 32955679 DOI: 10.1007/s00109-020-01973-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/10/2020] [Accepted: 08/27/2020] [Indexed: 12/19/2022]
Abstract
The expression of inducible nitric oxide (NO) synthase (iNOS) in human bladder cancer (BC) is a poor prognostic factor associated with invasion and tumor recurrence. Here, we evaluated the relevance of iNOS expression in BC progression and in cancer stem cell (CSC) maintenance in a murine BC model. Also, iNOS expression and CSC markers were analyzed in human BC samples. iNOS inhibitors (L-NAME or 1400W) or shRNA were used on murine BC model with different iNOS expressions and invasiveness grades: MB49 (iNOS+, non-muscle invasive (NMI)) and MB49-I (iNOS++, muscle invasive (MI)), in order to analyzed cell proliferation, tumor growth, angiogenesis, number of CSC, and pluripotential marker expression. iNOS, SOX2, Oct4, and Nanog expressions were also analyzed in human BC samples by qPCR and immunohistochemistry. iNOS inhibtion reduced parameters associated with tumor progression and reduced the number of CSC, wich resulted higher in MB49-I than in MB49, in concordance with the higher expression of SOX2, Oct4, and Nanog. The expression of SOX2 was notoriously diminished, when iNOS was inhibited only in the MI cell line. Similar results were observed in human samples, where MI tumors expressed higher levels of iNOS and pluripotential genes, in comparison to NMI tumors with a positive correlation between those and iNOS, suggesting that iNOS expression is associated with CSC. iNOS plays an important role in BC progression and CSC maintenance. Its inhibition could be a potential therapeutic target to eradicate CSC, responsible for tumor recurrences. KEY MESSAGES: • iNOS expression is involved in bladder tumor development, growth, and angiogenesis. • iNOS expression is involved in bladder cancer stem cell generation and maintenance, playing an important role regulating their self-renewal capacity, especially in muscle invasive murine bladder cancer cells. • iNOS expression is higher in human muscle invasive tumors, in association with a high expression of pluripotential genes, especially of SOX2.
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Affiliation(s)
- Denise Belgorosky
- Research Area, Instituto de Oncología Ángel H. Roffo (IOAHR), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Julie Girouard
- Medical Biology Department, Groupe de Recherche en Signalisation Cellulaire (GRSC), Université du Quebec a Trois-Rivières, Trois-Rivières, QC, Canada
| | - Yanina Veronica Langle
- Research Area, Instituto de Oncología Ángel H. Roffo (IOAHR), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jovane Hamelin-Morrissete
- Medical Biology Department, Groupe de Recherche en Signalisation Cellulaire (GRSC), Université du Quebec a Trois-Rivières, Trois-Rivières, QC, Canada
| | - Lina Marino
- Pathology Department, IOAHR, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Eduardo Imanol Agüero
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Héctor Malagrino
- Urology Department, IOAHR, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carlos Reyes-Moreno
- Medical Biology Department, Groupe de Recherche en Signalisation Cellulaire (GRSC), Université du Quebec a Trois-Rivières, Trois-Rivières, QC, Canada
| | - Ana María Eiján
- Research Area, Instituto de Oncología Ángel H. Roffo (IOAHR), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
- Área Investigaciones, Instituto de Oncología "Ángel H. Roffo", Av. San Martín 5481, CP1417DTB, Buenos Aires, Argentina.
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Mari A, Muto G, Di Maida F, Tellini R, Bossa R, Bisegna C, Campi R, Cocci A, Viola L, Grosso A, Scelzi S, Lapini A, Carini M, Minervini A. Oncological impact of inflammatory biomarkers in elderly patients treated with radical cystectomy for urothelial bladder cancer. Arab J Urol 2020; 19:2-8. [PMID: 33763243 PMCID: PMC7954471 DOI: 10.1080/2090598x.2020.1814974] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Objective To evaluate the impact of preoperative markers of systemic inflammation on complications and oncological outcomes in patients aged ≥75 years treated with radical cystectomy (RC) for urothelial bladder cancer (UBC). Patients and methods The clinical data of 694 patients treated with open RC for UBC at our institution between January 2008 and December 2015 were retrospectively reviewed. Patients aged <75 years, with distant metastases, other-than-urothelial histological type, comorbidities that could affect the systemic inflammatory markers, and patients who received neoadjuvant chemotherapy were excluded. Multivariable regression models were built for the prediction of major postoperative surgical complications, disease recurrence, cancer-specific mortality (CSM), and overall mortality (OM). Results The median (interquartile range [IQR]) age at surgery was 79 (75–83) years. Major postoperative surgical complications were registered in 41.9% of the patients. The 5-year overall survival, cancer-specific survival and recurrence-free survival rates were 42.4% (95% confidence interval [CI] 34.7–49.9%), 70.3% (95% CI 62.3–76.9%), and 59.8% (95% CI 52.4–66.5), respectively. At multivariable analysis, higher levels of fibrinogen and a modified Glasgow Prognostic Score (mGPS) of 1 and 2 at baseline were independently associated with higher risk of major postoperative complications and of CSM. The inclusion of mGPS and fibrinogen to a standard multivariable model for recurrence and for CSM increased discrimination from 69.4% to 73.0% and from 71.3% to 73.9%, respectively. Preoperative neutrophil-to-lymphocyte ratio of >3 was independently associated with OM (hazard ratio 1.38, 95% CI 1.01–1.77; P = 0.01). Conclusions In a cohort of elderly patients with UBC treated with RC, fibrinogen and mGPS appeared to be the most relevant prognostic measurements and increased the accuracy of clinicopathological preoperative models to predict major postoperative complications, disease recurrence and mortality. Abbreviations ASA: American Society of Anesthesiologists; CCI: Charlson Comorbidity Index; CIS: carcinoma in situ; CRP: C-reactive protein; CSM: cancer-specific mortality; CSS: cancer-specific survival; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HDL: high-density lipoprotein; (S)HR: (subdistribution) hazard ratio; LND: lymphadenectomy; LVI: lymphovascular invasion; mGPS: modified Glasgow Prognostic Score; NLR: neutrophil-to-lymphocyte ratio; NOC: non-organ-confined; OM: overall mortality; OR: odds ratio; OS: overall survival; RC: radical cystectomy; RNU: radical nephroureterectomy; UBC: urothelial bladder cancer; UTUC: upper urinary tract urothelial carcinoma
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Affiliation(s)
- Andrea Mari
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Gianluca Muto
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Fabrizio Di Maida
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Riccardo Tellini
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Riccardo Bossa
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Claudio Bisegna
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Riccardo Campi
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Andrea Cocci
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Lorenzo Viola
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Antonio Grosso
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Sabino Scelzi
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alberto Lapini
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy
| | - Marco Carini
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Andrea Minervini
- Unit of Oncologic Minimally-Invasive Urology and Andrology, Careggi Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Ikarashi N, Hoshino M, Ono T, Toda T, Yazawa Y, Sugiyama K. A Mechanism by which Ergosterol Inhibits the Promotion of Bladder Carcinogenesis in Rats. Biomedicines 2020; 8:biomedicines8070180. [PMID: 32605038 PMCID: PMC7400612 DOI: 10.3390/biomedicines8070180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/24/2020] [Accepted: 06/25/2020] [Indexed: 11/25/2022] Open
Abstract
We previously showed that ergosterol has an inhibitory effect on bladder carcinogenesis. In this study, we aimed to elucidate the molecular mechanism by which ergosterol inhibits bladder carcinogenesis using a rat model of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder cancer. The messenger ribonucleic acid (mRNA) expression level of the cell cycle-related gene cyclin D1 and inflammation-related gene cyclooxygenase-2 in bladder epithelial cells was significantly increased in the carcinogenesis group compared with the control group. In contrast, in ergosterol-treated rats, these increases were significantly suppressed. Ergosterol did not affect the plasma testosterone concentration or the binding of dihydrotestosterone to androgen receptor (AR). The mRNA expression levels of 5α-reductase type 2 and AR were higher in the carcinogenesis group than in the control group but were significantly decreased by ergosterol administration. These results suggest that ergosterol inhibits bladder carcinogenesis by modulating various aspects of the cell cycle, inflammation-related signaling, and androgen signaling. Future clinical application of the preventive effect of ergosterol on bladder carcinogenesis is expected.
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Affiliation(s)
- Nobutomo Ikarashi
- Department of Biomolecular Pharmacology, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
- Correspondence: (N.I.); (K.S.); Tel.: +81-3-5498-5918 (N.I.)
| | - Motohiro Hoshino
- Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; (M.H.); (T.O.)
| | - Tetsuya Ono
- Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan; (M.H.); (T.O.)
| | - Takahiro Toda
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan;
| | - Yasuharu Yazawa
- Department of Clinical Pharmaceutics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan;
| | - Kiyoshi Sugiyama
- Department of Functional Molecular Kinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan
- Correspondence: (N.I.); (K.S.); Tel.: +81-3-5498-5918 (N.I.)
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Mukae Y, Miyata Y, Nakamura Y, Araki K, Otsubo A, Yuno T, Mitsunari K, Matsuo T, Ohba K, Sakai H. Pathological roles of c-Met in bladder cancer: Association with cyclooxygenase-2, heme oxygenase-1, vascular endothelial growth factor-A and programmed death ligand 1. Oncol Lett 2020; 20:135-144. [PMID: 32565941 PMCID: PMC7285828 DOI: 10.3892/ol.2020.11540] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 02/18/2020] [Indexed: 02/02/2023] Open
Abstract
c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P=0.021), as well as the expression levels of HO-1 (P=0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P=0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P=0.006 and P=0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P=0.045 and P=0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.
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Affiliation(s)
- Yuta Mukae
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Yasuyoshi Miyata
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Yuichiro Nakamura
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kyohei Araki
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Asato Otsubo
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Tsutomu Yuno
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kensuke Mitsunari
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Tomohiro Matsuo
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Kojiro Ohba
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
| | - Hideki Sakai
- Department of Urology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501, Japan
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Luo J, Xu X. Dietary fiber intake and the risk of bladder cancer in the Prostate, Lung, Colorectal and Ovarian (PLCO) cohort. Carcinogenesis 2020; 41:478-482. [PMID: 31872237 DOI: 10.1093/carcin/bgz187] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/15/2019] [Accepted: 11/14/2019] [Indexed: 11/13/2022] Open
Abstract
Dietary fiber intake has been implicated as a protective factor for several human cancers in multiple epidemiologic studies. However, little is known about the effect of fiber intake on bladder cancer. This study examines the association between dietary fiber intake and bladder cancer risk among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 101 721 participants were included in this study as they completed both the baseline questionnaire and the diet history questionnaire (cancer free before completion of the diet history questionnaire). Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. After a median of 12.5 years of follow-up, 776 new cases of bladder cancer were identified. Higher intake of total fiber, insoluble fiber and soluble fiber were not significantly associated with a reduced risk of bladder cancer. The multi-adjusted HRs (95 CIs) of highest versus lowest tertile of intake were 0.83 (0.66-1.04) for total fiber (P for trend = 0.098), 0.83 (95% CI: 0.67-1.03) for insoluble fiber (P for trend = 0.092) and 0.86 (95% CI: 0.68-1.08) for soluble fiber (P for trend = 0.168), respectively. There was no significant interaction of potential confounders, including education, body mass index and smoking status, with total fiber intake on bladder cancer risk. In summary, the findings of this prospective study show that there is no obvious evidence for a link between dietary fiber consumption and bladder cancer risk. Further large cohort studies are warranted to confirm these findings.
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Affiliation(s)
- Jindan Luo
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xin Xu
- Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Gakis G, Hassan FN, Schmid MA, Ölschläger M, Hackenberg S, Stenzl A, Renninger M. Prognostic significance of previous tonsillectomy after radical cystectomy for bladder cancer. Scand J Urol 2020; 54:297-303. [PMID: 32500778 DOI: 10.1080/21681805.2020.1773530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Introduction: To examine whether previous tonsillectomy (TE) impacts on survival after radical cystectomy (RC) for bladder cancer (BC).Patients and Methods: A total of 320 patients were staged cM0 and underwent RC for BC between 2002 and 2013. We retrospectively investigated whether patients had undergone TE prior to RC. Chi-square/Fisher-Exact test was carried out to compare clinicopathological features between the TE- and non-TE-group. Kaplan-Meier analysis with log-rank test was used to estimate recurrence-free survival (RFS) and multivariable Cox-regression analysis of risk factors of recurrence. The median follow-up was 31 months (interquartile range: 9-54).Results: A history of TE was present in 18 of the 320 patients (5.6%). All TEs were performed for benign conditions. TE prior to RC was associated with a history of appendectomy (p = 0.045), lower age at RC (p = 0.029), tumor unifocality (p < 0.001), advanced histopathological tumor stage (p = 0.015), non-pure urothelial carcinoma (p = 0.025), lymphovascular invasion (p = 0.035) and receipt of palliative chemotherapy (p = 0.004). The 3-year RFS was 39.2% for patients with previous TE and 62.4% for those without (p = 0.008). In multivariable analysis, adjusted for all significant parameters of univariable analysis, lymph-node tumor involvement (p = 0.017), positive surgical margins (p = 0.047), tumor grade (p = 0.032), advanced tumor stage (≥pT3a; p = 0.049) and a history of TE (p = 0.021) remained independent prognosticators of recurrence.Conclusion: In this series, previous TE was an independent predictor of recurrence after RC for BC. Further studies are needed to assess whether TE induces immunological alterations that might exert adverse effects on cancer progression of patients with invasive BC.
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Affiliation(s)
- Georgios Gakis
- Department of Urology and Pediatric Urology, University Hospital of Würzburg, Julius-Maximilians University, Wuerzburg, Germany.,Department of Urology, University Hospital of Würzburg, Eberhard-Karls University, Tuebingen, Germany
| | - Fahmy Nabil Hassan
- Department of Urology and Pediatric Urology, University Hospital of Würzburg, Julius-Maximilians University, Wuerzburg, Germany.,Department of Urology, University Hospital of Würzburg, Eberhard-Karls University, Tuebingen, Germany
| | - Manuel Alexander Schmid
- Department of Urology, University Hospital of Würzburg, Eberhard-Karls University, Tuebingen, Germany
| | - Markus Ölschläger
- Department of Urology and Pediatric Urology, University Hospital of Würzburg, Julius-Maximilians University, Wuerzburg, Germany
| | - Stephan Hackenberg
- Department of ENT, University Hospital of Würzburg, Julius-Maximilians University, Wuerzburg, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital of Würzburg, Eberhard-Karls University, Tuebingen, Germany
| | - Markus Renninger
- Department of Urology, University Hospital of Würzburg, Eberhard-Karls University, Tuebingen, Germany
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Bourn J, Rathore K, Donnell R, White W, Uddin MJ, Marnett L, Cekanova M. Detection of carcinogen-induced bladder cancer by fluorocoxib A. BMC Cancer 2019; 19:1152. [PMID: 31775672 PMCID: PMC6882158 DOI: 10.1186/s12885-019-6366-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 11/15/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Conventional cystoscopy can detect advanced stages of bladder cancer; however, it has limitations to detect bladder cancer at the early stages. Fluorocoxib A, a rhodamine-conjugated analog of indomethacin, is a novel fluorescent imaging agent that selectively targets cyclooxygenase-2 (COX-2)-expressing cancers. METHODS In this study, we have used a carcinogen N-butyl-N-4-hydroxybutyl nitrosamine (BBN)-induced bladder cancer immunocompetent mouse B6D2F1 model that resembles human high-grade invasive urothelial carcinoma. We evaluated the ability of fluorocoxib A to detect the progression of carcinogen-induced bladder cancer in mice. Fluorocoxib A uptake by bladder tumors was detected ex vivo using IVIS optical imaging system and Cox-2 expression was confirmed by immunohistochemistry and western blotting analysis. After ex vivo imaging, the progression of bladder carcinogenesis from normal urothelium to hyperplasia, carcinoma-in-situ and carcinoma with increased Ki67 and decreased uroplakin-1A expression was confirmed by histology and immunohistochemistry analysis. RESULTS The specific uptake of fluorocoxib A correlated with increased Cox-2 expression in progressing bladder cancer. In conclusion, fluorocoxib A detected the progression of bladder carcinogenesis in a mouse model with selective uptake in Cox-2-expressing bladder hyperplasia, CIS and carcinoma by 4- and 8-fold, respectively, as compared to normal bladder urothelium, where no fluorocoxib A was detected. CONCLUSIONS Fluorocoxib A is a targeted optical imaging agent that could be applied for the detection of Cox-2 expressing human bladder cancer.
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Affiliation(s)
- Jennifer Bourn
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, 37996, USA.,UT-ORNL Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN, 37996, USA.,Present address: Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH, 45221, USA
| | - Kusum Rathore
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, 37996, USA.,Present address: The University of Tennessee Research Foundation, Knoxville, TN, 37996, USA
| | - Robert Donnell
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, 37996, USA
| | - Wesley White
- Department of Urology, The University of Tennessee, Graduate School of Medicine, Knoxville, TN, 37920, USA
| | - Md Jashim Uddin
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Lawrence Marnett
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Maria Cekanova
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, 37996, USA. .,UT-ORNL Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN, 37996, USA.
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Schubert T, Renninger M, Schmid MA, Hassan FN, Sokolakis I, Fahmy O, Hatzichristodoulou G, Stenzl A, Gakis G. Prognostic impact of tumor-associated immune cell infiltrates at radical cystectomy for bladder cancer. Urol Oncol 2019; 38:4.e7-4.e15. [PMID: 31537484 DOI: 10.1016/j.urolonc.2019.08.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/10/2019] [Accepted: 08/19/2019] [Indexed: 11/25/2022]
Abstract
OBJECTIVES To assess whether the presence and location of tumor-associated immune cell infiltrates (TAIC) on histological slides obtained from cystectomy specimens impacts on oncological outcomes of patients with bladder cancer (BC). MATERIAL AND METHODS A total of 320 consecutive patients staged with cM0 bladder cancer underwent radical cystectomy (RC) between 2004 and 2013. The presence of TAIC (either located peritumorally [PIC] and/or intratumorally [IIC]) on histological slides was retrospectively assessed and correlated with outcomes. Kaplan-Meier analyses were used to estimate the impact of TAIC on recurrence-free (RFS), cancer-specific (CSS), and overall survival (OS). Multivariable Cox-regression analysis was carried out to evaluate risk factors of recurrence. The median follow-up was 37 months (IQR: 10-55). RESULTS Of the 320 patients, 42 (13.1%) exhibited IIC, 141 (44.1%) PIC and 137 (42.8%) no TAIC in the cystectomy specimens. Absence of TAIC was associated with higher ECOG performance status (P = 0.042), histologically advanced tumor stage (≥pT3a; P < 0.001), lymph node tumor involvement (pN+; P = 0.022), positive soft tissue surgical margins (P = 0.006), lymphovascular invasion (P < 0.001), and elevated serum C-reactive protein levels (P < 0.001). The rate of never smokers was significantly higher in the IIC-group (64.3%) compared to the PIC-group (39.7%, P = 0.007) and those without TAIC (35.8%, P = 0.001). The 3-year RFS/CSS/OS was 73.9%/88.5%/76.7% for patients with IIC, 69.4%/85.2%/70.1% for PIC and 47.6%/68.5%/56.1% for patients without TAIC (P < 0.001/<0.001/0.001 for TAIC vs. no TAIC). In multivariable analysis, adjusted for all significant parameters of univariable analysis, histologically advanced tumor stage (P = 0.003), node-positive disease (P = 0.002), and the absence of TAIC (P = 0.035) were independent prognosticators for recurrence. CONCLUSIONS In this analysis, the presence and location of TAIC in cystectomy specimens was a strong prognosticator for RFS after RC. This finding suggests that the capability of immune cells to migrate into the tumor at the time of RC is prognostically important in invasive bladder cancer.
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Affiliation(s)
- Tina Schubert
- Department of Urology and Pediatric Urology, University Hospital of Wuerzburg, Julius-Maximilians University, Wuerzburg, Germany; Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany
| | - Markus Renninger
- Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany
| | - Manuel Alexander Schmid
- Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany
| | - Fahmy Nabil Hassan
- Department of Urology and Pediatric Urology, University Hospital of Wuerzburg, Julius-Maximilians University, Wuerzburg, Germany; Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany
| | - Ioannis Sokolakis
- Department of Urology and Pediatric Urology, University Hospital of Wuerzburg, Julius-Maximilians University, Wuerzburg, Germany
| | - Omar Fahmy
- Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany; Department of Urology, University Putra Malaysia (UPM), Serdang, Selangor, Malaysia
| | - Georgios Hatzichristodoulou
- Department of Urology and Pediatric Urology, University Hospital of Wuerzburg, Julius-Maximilians University, Wuerzburg, Germany
| | - Arnulf Stenzl
- Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany
| | - Georgios Gakis
- Department of Urology and Pediatric Urology, University Hospital of Wuerzburg, Julius-Maximilians University, Wuerzburg, Germany; Department of Urology, University Hospital of Tuebingen, Eberhard-Karls University, Tuebingen, Germany.
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Bourn J, Pandey S, Uddin J, Marnett L, Cekanova M. Detection of tyrosine kinase inhibitors-induced COX-2 expression in bladder cancer by fluorocoxib A. Oncotarget 2019; 10:5168-5180. [PMID: 31497247 PMCID: PMC6718263 DOI: 10.18632/oncotarget.27125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 07/17/2019] [Indexed: 01/02/2023] Open
Abstract
Among challenges of targeted therapies is the activation of alternative pro-survival signaling pathways in cancer cells, resulting in an acquired drug resistance. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer cells, making it an attractive molecular target for the detection and treatment of cancer. Fluorocoxib A is an optical imaging agent that selectively targets COX-2. In this study, we evaluated the ability of fluorocoxib A to monitor the responses of bladder cancer to targeted therapies in vivo. The effects of several tyrosine kinase inhibitors (TKIs: axitinib, AB1010, toceranib, imatinib, erlotinib, gefitinib, imatinib, sorafenib, vandetanib, SP600125, UO126, and AZD 5438) on COX-2 expression were validated in ten human and canine bladder cancer cell lines (J82, RT4, T24, UM-UC-3, 5637, SW780, TCCSUP, K9TCC#1Lillie, K9TCC#2Dakota, K9TCC#5Lilly) in vitro. The effects of TKIs on bladder cancer in vivo were evaluated using the COX-2-expressing K9TCC#5Lilly xenograft mouse model and detected by fluorocoxib A. The increased COX-2 expression was detected by all tested TKIs in at least one of the tested COX-2-expressing bladder cancer cell lines (5637, SW780, TCCSUP, K9TCC#1Lillie, K9TCC#2Dakota, and K9TCC#5Lilly) in vitro. In addition, fluorocoxib A uptake correlated with the AB1010- and imatinib-induced COX-2 expression in the K9TCC#5Lilly xenografts in vivo. In conclusion, these results indicate that fluorocoxib A could be used for the monitoring the early responses to targeted therapies in COX-2-expressing bladder cancer.
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Affiliation(s)
- Jennifer Bourn
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, USA.,University of Tennessee and Oak Ridge National Laboratory, Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN 37996, USA.,Current address: Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Sony Pandey
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, USA
| | - Jashim Uddin
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Lawrence Marnett
- A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Center for Molecular Toxicology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Maria Cekanova
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, USA.,University of Tennessee and Oak Ridge National Laboratory, Graduate School of Genome Science and Technology, The University of Tennessee, Knoxville, TN 37996, USA
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Buzatto AB, Elias F, Franzoni MS, Fonseca-Alves CE. Long-Term Survival of a Cat with Primary Leiomyosarcoma of the Urinary Bladder. Vet Sci 2019; 6:60. [PMID: 31252551 PMCID: PMC6789653 DOI: 10.3390/vetsci6030060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 06/18/2019] [Accepted: 06/26/2019] [Indexed: 01/07/2023] Open
Abstract
Primary bladder leiomyosarcoma was diagnosed in a four-year-old, mixed-breed, spayed female cat that presented with lethargy, stranguria, polyuria, hematuria, urinary incontinence and abdominal sensitivity. On abdominal ultrasound, the urinary bladder was observed to have a preserved anatomical position and a hyperechoic mass. The mass measured approximately 1.5 cm, was irregular, and arose from the mucosa of the bladder wall. Due to the evidence of a primary tumor in the urinary bladder, we conducted a partial cystectomy with a 1.0 cm surgical margin and performed histopathology and immunohistochemistry. The histopathology revealed a poorly differentiated malignant neoplasm, characterized by the proliferation of spindle cells with moderate nuclear pleomorphism, suggestive of leiomyosarcoma. Immunohistochemistry confirmed the histopathological diagnosis, showing positive staining for vimentin, desmin and alpha-smooth muscle actin and negative staining for S100, pan-cytokeratin and MyoD1. We also assessed the proliferative index by Ki67 staining and found that 57% of the neoplastic cells were positive for Ki67. We conducted clinical follow-ups every three months in the first year and every six months thereafter. The patient showed no signs of recurrence after 48 months. The surgery was sufficient to treat the leiomyosarcoma, and adjuvant chemotherapy was not necessary in this case.
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Affiliation(s)
- Anneliese Baetz Buzatto
- Veterinary Oncology Specialization Course, Instituto Bioethicus, Botucatu SP 18605-545, Brazil
| | - Fabiana Elias
- Superintendencia Unidade Hospitalar Veterinaria Universitaria, Federal University of the Fronteira Sul, Realeza PR 85770-000, Brazil
| | - Mayara Simão Franzoni
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, University of Sao Paulo State - UNESP, Botucatu SP 18618-681, Brazil
| | - Carlos Eduardo Fonseca-Alves
- Veterinary Oncology Specialization Course, Instituto Bioethicus, Botucatu SP 18605-545, Brazil.
- Department of Veterinary Surgery and Anesthesiology, School of Veterinary Medicine and Animal Science, University of Sao Paulo State - UNESP, Botucatu SP 18618-681, Brazil.
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Zhang Q, Mao Z, Sun J. NF-κB inhibitor, BAY11-7082, suppresses M2 tumor-associated macrophage induced EMT potential via miR-30a/NF-κB/Snail signaling in bladder cancer cells. Gene 2019; 710:91-97. [PMID: 31002892 DOI: 10.1016/j.gene.2019.04.039] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/24/2019] [Accepted: 04/15/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Chronic inflammatory microenvironment has been shown to play a key role in initiating tumorigenesis and facilitating malignant progression. Primary tumors surrounded with and infiltrated by tumor-associated macrophages (TAMs) significantly promote the epithelial-to-mesenchymal transition (EMT) and distant metastasis in urothelial bladder cancer. METHODS In this study, we aimed to explore the potential of targeting TAMs for the treatment of malignant bladder cancer. RESULTS First, we found a higher number of TAMs, CD68 (pan-macrophage marker), and clever-1 (M2 macrophage marker) was associated with a higher pT category and grade in a cohort of 108 patients. In vitro assays showed that the co-culture of TAMs promoted the metastatic potential in HTB-1 and T24 by up-regulating EMT markers including Snail, VEGF and Vimentin, as well as oncogenic markers such as β-catenin and NF-κB. More importantly, M2 co-cultured HTB-1 and T24 showed an increased level of metastatic microRNA, miR-30. Silencing of miR-30 resulted in the reduced metastatic potential, migration/invasion, in association with the decreased expression of Twist1 and Vimentin. The addition of BAY11-7082 into the TAM/cancer co-culture system significantly reduced the M2 phenotype and tumorigenic properties. Coincidentally, miR-30a level was significantly lowered in the presence of BAY11-7082. CONCLUSION Our study demonstrated that AMs promoted metastatic potential of bladder cancer cells via promoting EMT through the increase of miR-30a. BAY11-7082 treatment suppressed both oncogenic and metastatic potential in bladder cancer cells while preventing the M2 polarization of TAMs.
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Affiliation(s)
- Qi Zhang
- Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou 310014, China
| | - Zujie Mao
- Department of Urology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Juan Sun
- Department of Ultrasonography, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
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The impact of postoperative inflammatory biomarkers on oncologic outcomes of bladder cancer. Prog Urol 2019; 29:270-281. [PMID: 30954405 DOI: 10.1016/j.purol.2019.02.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/08/2019] [Accepted: 02/14/2019] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The clinical impact of inflammatory biomarkers has been evaluated in urothelial bladder cancer. However, data are limited to preoperative values and there is paucity of evidence of the role of postoperative measurement of those biomarkers. The aim of the current study was to determine the association of inflammatory biomarkers as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), hemoglobin to platelet ratio (HPR) and C-reactive protein (CRP), before and after radical cystectomy, with recurrence and survival of bladder cancer. MATERIAL AND METHODS We prospectively evaluated 134 patients undergoing radical cystectomy for invasive bladder cancer between January 2013 and January 2018. The inflammatory biomarkers were measured 10days before surgery and at 1, 6 and 12months postoperatively. Kaplan-Meier curves and Cox proportional hazards and logistic regression models were used to evaluate the association between the different inflammatory biomarkers and recurrence free survival (RFS), cancer specific survival (CSS) and overall survival (OS). RESULTS The median follow-up time was 21.1months (5-37 mo). On multivariate analysis, preoperative NLR>3.88 was associated to locally-advanced disease (>pT3) and NLR>3.88 and HPR<0.039 were significantly associated to node positive disease. Postoperative NLR at 3months>4.68 (HR: 2.37, 95% CI: 1.08-4.47, P=0.03) was associated with a reduced RFS. A postoperative NLR at 3months>4.68 (P=0.04) and a postoperative HPR at 3months<0.029 (P=0.001) were associated with a significant reduction in CSS and OS. CONCLUSION Postoperative NLR and HPR at 3months appear to be closely associated with RFS, CSS and OS. Further studies are needed on these postoperative markers to establish the potential impact of these inflammatory biomarkers on a tailored therapeutic approach for each patient. LEVEL OF EVIDENCE 3.
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Chan TC, Li CF, Ke HL, Wei YC, Shiue YL, Li CC, Yeh HC, Lee HY, Huang SK, Wu WJ, Li WM. High TNFAIP6 level is associated with poor prognosis of urothelial carcinomas. Urol Oncol 2019; 37:293.e11-293.e24. [PMID: 30595463 DOI: 10.1016/j.urolonc.2018.12.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 12/03/2018] [Accepted: 12/08/2018] [Indexed: 11/22/2022]
Abstract
PURPOSE Inflammatory responses affect each stage of carcinogenesis, from initiation, through invasion, to metastasis. Studies have shown that chronic inflammation induced by environmental and occupational exposures increase the risk of developing urothelial carcinoma (UC). Using a published UC transcriptome (GSE32894), we identified that among genes associated with inflammatory response (GO:0006954), TNFAIP6 was significantly upregulated during UC progression. Therefore, we investigated the association of TNFAIP6 with disease features, metastasis and survival in our well-characterized cohort of UC. METHODS We determined TNFAIP6 expression in 340 upper urinary tract UCs (UTUC) and 295 urinary bladder UCs (UBUC) using immunohistochemistry and evaluated the results using H-score. TNFAIP6 expression correlated with clinicopathological features, disease-specific survival, and metastasis-free survival. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards model. RESULTS High TNFAIP6 expression was significantly associated with advanced pathological stage, lymph node metastasis, perineural invasion, vascular invasion, and high mitotic activity. Multivariate analysis identified high TNFAIP6 expression as an independent predictor of disease-specific survival (hazard ratio in UTUC: 2.891, P = 0.003; in UBUC: 2.175, P = 0.017) and metastasis-free survival (hazard ratio in UTUC: 3.803, P < 0.001; in UBUC: 3.845, P < 0.001). CONCLUSION High TNFAIP6 expression is associated with aggressive clinicopathological features and poor prognosis in UCs, suggesting it may serve as a novel prognosticator and treatment target. TNFAIP6 immunostaining may be used with current pathological examinations for better risk stratification for UCs.
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Affiliation(s)
- Ti-Chun Chan
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan; Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan; Natioanl Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan
| | - Hung-Lung Ke
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Ching Wei
- Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Ching-Chia Li
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsin-Chih Yeh
- Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Hsiang-Ying Lee
- Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Steven-K Huang
- Division of Urology, Chi Mei Medical Center, Tainan, Taiwan
| | - Wen-Jeng Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Ming Li
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan.
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Iacona JR, Lutz CS. miR-146a-5p: Expression, regulation, and functions in cancer. WILEY INTERDISCIPLINARY REVIEWS-RNA 2019; 10:e1533. [PMID: 30895717 DOI: 10.1002/wrna.1533] [Citation(s) in RCA: 121] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/19/2019] [Accepted: 02/20/2019] [Indexed: 12/14/2022]
Abstract
Cancer as we know it is actually an umbrella term for over 100 very unique malignancies in various tissues throughout the human body. Each type, and even subtype of cancer, has different genetic, epigenetic, and other cellular events responsible for malignant development and metastasis. Recent work has indicated that microRNAs (miRNAs) play a major role in these processes, sometimes by promoting cancer growth and other times by suppressing tumorigenesis. miRNAs are small, noncoding RNAs that negatively regulate expression of specific target genes. This review goes into an in-depth look at the most recent finding regarding the significance of one particular miRNA, miR-146a-5p, and its involvement in cancer. Target gene validation and pathway analysis have provided mechanistic insight into this miRNA's purpose in assorted tissues. Additionally, this review outlines novel findings that suggest miR-146a-5p may be useful as a noninvasive biomarker and as a targeted therapeutic in several cancers. This article is categorized under: RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.
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Affiliation(s)
- Joseph R Iacona
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School and the School of Graduate Studies, Health Sciences Campus - Newark, Newark, New Jersey
| | - Carol S Lutz
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School and the School of Graduate Studies, Health Sciences Campus - Newark, Newark, New Jersey
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Bausch K, Roth E, Heinz S, Horst D, Mathia S, Vlajnic T, Bubendorf L, Westhoff T, Wetterauer C, Seifert HH, Ebbing J. Urinary Calprotectin loses specificity as tumour marker due to sterile leukocyturia associated with bladder cancer. PLoS One 2019; 14:e0213549. [PMID: 30870488 PMCID: PMC6417709 DOI: 10.1371/journal.pone.0213549] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 02/24/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Urinary Calprotectin, a mediator of the innate immune system, has been identified as a biomarker in bladder cancer. Our aim was to investigate the association between sterile leukocyturia and urinary Calprotectin in low-grade and high-grade bladder cancer. MATERIALS AND METHODS We performed a prospective cross-sectional study including 52 patients with bladder cancer and 40 healthy controls. Definition of sterile leukocyturia was > 5.0 leukocytes per visual field in absence of bacteriuria. RESULTS The rate of sterile leukocyturia in low-grade (60.0%) and high-grade (62.0%) bladder cancer was comparable (p = 0.87). However, the median absolute urinary leukocyte count in patients with sterile leukocyturia was significantly higher in high-grade than in low-grade bladder cancer (p < 0.01). Spearman correlation revealed a significant correlation between urinary Calprotectin and leucocyte concentration (R = 0.4, p < 0.001). Median urinary Calprotectin concentration was 4.5 times higher in bladder cancer patients with than in patients without sterile leukocyturia (p = 0.03). Subgroup analysis revealed a significant difference in urinary Calprotectin regarding the presence of sterile leukocyturia in high-grade patients (596.8 [91.8-1655.5] vs. 90.4 [28.0-202.3] ng ml-1, p = 0.02). Multivariate analysis identified the leukocyte concentration to be the only significant impact factor for urinary Calprotectin (OR 3.2, 95% CI 2.5-3.8, p = 0.001). Immunohistochemistry showed Calprotectin positive neutrophils and tumour cells in high-grade bladder cancer with sterile leukocyturia. CONCLUSIONS Urinary Calprotectin cannot be regarded as a specific tumour marker for bladder cancer, but rather as a surrogate parameter for tumour inflammation.
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Affiliation(s)
- Kathrin Bausch
- Urological University-Clinic Basel-Liestal, University Hospital Basel, Basel, Switzerland
- * E-mail:
| | | | | | - David Horst
- Department of Pathology, University Hospital Charité Berlin, Berlin, Germany
| | - Susanne Mathia
- Department of Nephrology, University Hospital Charité Berlin, Berlin, Germany
| | - Tatjana Vlajnic
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Lukas Bubendorf
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Timm Westhoff
- Department of Nephrology, Marien Hospital Herne, University Clinic of the Ruhr-University Bochum, Herne, Germany
| | - Christian Wetterauer
- Urological University-Clinic Basel-Liestal, University Hospital Basel, Basel, Switzerland
| | - Hans Helge Seifert
- Urological University-Clinic Basel-Liestal, University Hospital Basel, Basel, Switzerland
| | - Jan Ebbing
- Urological University-Clinic Basel-Liestal, University Hospital Basel, Basel, Switzerland
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Aghaalikhani N, Rashtchizadeh N, Shadpour P, Allameh A, Mahmoodi M. Cancer stem cells as a therapeutic target in bladder cancer. J Cell Physiol 2018; 234:3197-3206. [PMID: 30471107 DOI: 10.1002/jcp.26916] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 06/13/2018] [Indexed: 12/13/2022]
Abstract
Bladder cancer is one of the most prevalent genitourinary cancers responsible for about 150,000 deaths per year worldwide. Currently, several treatments, such as endoscopic and open surgery, appended by local or systemic immunotherapy, chemotherapy, and radiotherapy are used to treat this malignancy. However, the differences in treatment outcome among patients suffering from bladder cancer are considered as one of the important challenges. In recent years, cancer stem cells, representing a population of undifferentiated cells with stem-cell like properties, have been eyed as a major culprit for the high recurrence rate in superficial papillary bladder cancer. Cancer stem cells have been reported to be resistant to conventional treatments, such as chemotherapy, radiation, and immunotherapy, which induce selective pressure on tumoral populations resulting in selection and growth of the resistant cells. Therefore, targeting the therapeutic aspects of cancer stem cells in bladder cancer may be promising. In this study, we briefly discuss the biology of bladder cancer and then address the possible relationship between molecular biology of bladder cancer and cancer stem cells. Subsequently, the mechanisms of resistance applied by cancer stem cells against the conventional therapeutic tools, especially chemotherapy, are discussed. Moreover, by emphasizing the biomarkers described for cancer stem cells in bladder cancer, we have provided, described, and proposed targets on cancer stem cells for therapeutic interventions and, finally, reviewed some immunotargeting strategies against bladder cancer stem cells.
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Affiliation(s)
- Nazi Aghaalikhani
- Department of Clinical Biochemistry and Laboratory Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nadereh Rashtchizadeh
- Department of Clinical Biochemistry and Laboratory Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pejman Shadpour
- Hasheminejad Kidney Centre (HKC), Hospital Management Research Centre (HMRC), University of Medical Sciences (IUMS), Tehran, Iran
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Marzieh Mahmoodi
- Faculty of Health and Nutrition, Bushehr University of Medical Sciences, Bushehr, Iran
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Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature. Pharmaceuticals (Basel) 2018; 11:ph11040101. [PMID: 30314310 PMCID: PMC6316056 DOI: 10.3390/ph11040101] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/05/2018] [Accepted: 10/09/2018] [Indexed: 12/12/2022] Open
Abstract
Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE₂) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.
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