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Molecular Biomarkers and Imaging Markers in the Prediction, Diagnosis, and Prognosis of Bladder Cancer

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Editorial14 October 2022
Editorial: Molecular biomarkers and imaging markers in the prediction, diagnosis, and prognosis of bladder cancer
Yongwen Luo, Fang-Ming Deng, Yi Zhangand Yu Xiao

4 Authors

Bladder cancer (BLCA) is a common malignant tumor in the urinary system. BLCA is divided into muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC) 1 . Approximately 70% of BLCA patients are initially diagnosed with NMIBC, but 50-70% of patients relapse after treatment, and 10-20% of patients progress to MIBC. The 5-year survival rate for patients with MIBC is about 50% 2,3 . Nowadays there is still a lack of public recognized, universally applicable diagnosis and prognostic markers for BLCA.In this Research Topic, we compiled seventeen research articles and one review that summarized new advances about molecular biomarkers and imaging markers in the prediction, diagnosis, and prognosis of BLCA. In conclusion, the collections of research articles and reviews under this Research Topic present novel insights on the prediction, diagnosis, and prognosis of bladder cancer. It will hopefully encourage us to explore molecular targets from various perspectives and ultimately promote the diagnosis and treatment of BLCA.

2,462 views

1 citations

Ferroptosis Patterns and Tumor Microenvironment Infiltration Characterization in Bladder Cancer
ORIGINAL RESEARCH
21 March 2022
Ferroptosis Patterns and Tumor Microenvironment Infiltration Characterization in Bladder Cancer
Qi-Dong Xia, 7 more and Shao-Gang Wang

9 Authors

Background: Ferroptosis is a unique iron-dependent form of cell death and bladder cancer (BCa) is one of the top ten most common cancer types in the world. But the role of ferroptosis in shaping tumor microenvironment and influencing tumor clinicopathological features remains unknown. Methods: Using the data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), we comprehensively evaluated the ferroptosis patterns of 570 bladder cancer samples based on 234 validated ferroptosis genes reported in the FerrDb database, and systematically correlated these ferroptosis patterns with tumor microenvironment (TME) cell-infiltrating characteristics. The ferroptosis score was constructed to quantify ferroptosis patterns of individuals using principal component analysis (PCA) algorithms. Results: Four distinct ferroptosis patterns and two gene clusters were finally determined. Significant differences in clinical characteristics and the prognosis of patients were found among different ferroptosis patterns and gene clusters, so were in the mRNA transcriptome and the landscape of TME immune cell infiltration. We also established a set of scoring system to quantify the ferroptosis pattern of individual patients with bladder cancer named ferroptosis score, which was discovered to be tightly interacted with clinical signatures such as TNM category and tumor grade, and could predict the prognosis of patients with BCa. Moreover, tumor mutation burden (TMB) was positively correlated to ferroptosis score and low ferroptosis score was related to better response to immunotherapy using PD-1 blockade. Finally, we also found there existed a positive correlation between sensitivity to cisplatin chemotherapy and ferroptosis score. Conclusions: Our work demonstrated and interpreted the complicated regulation mechanisms of ferroptosis on tumor microenvironment, and better understanding and evaluating ferroptosis patterns could be helpful in guiding clinical therapeutic strategy and improving the prognosis of patients with bladder cancer.

6,135 views

28 citations

ORIGINAL RESEARCH
2 March 2022
Development and Validation of Ferroptosis-Related LncRNA Biomarker in Bladder Carcinoma
Yiru Wang, 6 more and Hang Yin

8 Authors

4,344 views

18 citations

ORIGINAL RESEARCH
2 March 2022
Dynamic Changes in Myofibroblasts Affect the Carcinogenesis and Prognosis of Bladder Cancer Associated With Tumor Microenvironment Remodeling
YiHeng Du, 7 more and BoXin Xue

9 Authors

2,970 views

22 citations

ORIGINAL RESEARCH
23 February 2022
Integrated Analysis of Energy Metabolism Signature-Identified Distinct Subtypes of Bladder Urothelial Carcinoma
Fan Zhang, 8 more and Xin Wei

10 Authors

4,285 views

7 citations

ORIGINAL RESEARCH
25 February 2022
Radiomics of Contrast-Enhanced Computed Tomography: A Potential Biomarker for Pretreatment Prediction of the Response to Bacillus Calmette-Guerin Immunotherapy in Non-Muscle-Invasive Bladder Cancer
Lei Ye, 8 more and Bin Song

10 Authors

3,007 views

9 citations

Identification and Quantification of Iron Metabolism Landscape on Therapy and Prognosis in Bladder Cancer
ORIGINAL RESEARCH
21 February 2022
Identification and Quantification of Iron Metabolism Landscape on Therapy and Prognosis in Bladder Cancer
Xiaodong Song, 11 more and Wen Song

13 Authors

The morbidity of bladder cancer (BLCA) is high and gradually elevating in recent years. BLCA is also characterized by high recurrence and high invasiveness. Due to the drug resistance and lack of effective prognostic indicators, the prognosis of patients with BLCA is greatly affected. Iron metabolism is considered to be a pivot of tumor occurrence, progression and tumor microenvironment (TME) in tumors, but there is few research in BLCA. Herein, we used univariate COX regression analysis to screen 95 prognosis-related IMRGs according to transcription RNA sequencing and prognosis information of the Cancer Genome Atlas (TCGA) database. TCGA-BLCA cohort was clustered into four distinct iron metabolism patterns (C1, C2, C3 and C4) by non-negative matrix factorization (NMF) algorithm. Survival analysis showed that C1 and C3 patterns had a better prognosis. GSVA analysis revealed that C2 and C4 patterns were mostly enriched in carcinogenic and immune activation pathways. ESTIMATE and ssGSEA analysis also confirmed the level of immune cell infiltration in C2 and C4 patterns significantly elevated. Moreover, the immune checkpoint genes in C2 and C4 patterns were observably overexpressed. Studies on somatic mutations showed that the tumor mutation burden (TMB) of C1 and C4 patterns was the lowest. Chemotherapy response assessment revealed that C2 pattern was the most sensitive to chemotherapy, while C3 pattern was the most insensitive. Then we established the IMRG prognosis signature (IMRGscore) by the least absolute shrinkage and selection operator (LASSO), including 13 IMRGs (TCIRG1, CTSE, ATP6V0A1, CYP2C8, RNF19A, CYP4Z1, YPEL5, PLOD1, BMP6, CAST, SCD, IFNG and ASIC3). We confirmed IMRGscore could be utilized as an independent prognostic indicator. Therefore, validation and quantification of iron metabolism landscapes will help us comprehend the formation of BLCA immunosuppressive microenvironment, guide the selection of chemotherapeutic drugs and immunotherapy, and predict the prognosis of patients.

5,823 views

15 citations

ORIGINAL RESEARCH
31 January 2022
Novel Non-Invasive Diagnosis of Bladder Cancer in Urine Based on Multifunctional Nanoparticles
Jinshan Xu, 8 more and Chuanliang Xu

10 Authors

4,322 views

7 citations

TNF Family–Based Signature Predicts Prognosis, Tumor Microenvironment, and Molecular Subtypes in Bladder Carcinoma
ORIGINAL RESEARCH
31 January 2022
TNF Family–Based Signature Predicts Prognosis, Tumor Microenvironment, and Molecular Subtypes in Bladder Carcinoma
Huihuang Li, 4 more and Cheng Zhao

6 Authors

Background: Tumor necrosis factor (TNF) family members play vital roles in cancer development and anti-tumor immune responses. However, the expression patterns, prognostic values and immunological characteristics of TNF members in bladder carcinoma (BLCA) remain unclear. Methods: The training cohort, TCGA-BLCA, was downloaded from The Cancer Genome Atlas (TCGA); another two Gene Expression Omnibus (GEO) datasets (GSE13507 and GSE32894) and the Xiangya cohort (RNA-seq cohort collected from our hospital) were used as the external validation cohort. The least absolute shrinkage and selection operator (LASSO) algorithm and cross-validation were used to screen variables. Cox regression model and random survival forest (RSF) were used to develop the risk score respectively. Then, we systematically correlated the TNF risk score with the tumor microenvironment (TME) cell infiltration, molecular subtypes of BLCA and the potential value for predicting the efficacy of immunotherapy. Results: We developed two TNF-based patterns, named TNF cluster 1 and TNF cluster 2. TNF cluster 1 exhibited poorer survival outcome and an inflamed TME characteristic compared to TNF cluster 2. We then filtered out 196 differential expressed genes (DEGs) between the two TNF clusters and applied the LASSO algorithm and cross-validation to screen out 22 genes to build the risk score. For risk score, we found that RSF exhibited higher efficacy than the cox regression model, and we chose the risk score developed by RSF for the following analysis. BLCA patients in the higher risk score group showed significantly poorer survival outcomes. Moreover, these results could be validated in the external validation cohorts, including the GSE13507, GSE32894 and Xiangya cohorts. Then, we systematically correlated the risk score with TME cell infiltration and found that it was positively correlated with the infiltration of a majority of immune cells. Also, a higher risk score indicated a basal subtype of BLCA. Notably, the relationship between risk score, TME cell infiltration and molecular subtypes could be validated in the Xiangya cohort. Conclusions: We developed and validated a robust TNF-based risk score, which could predict prognostic outcomes, TME and molecular subtypes of BLCA. However, the value of risk score predicting the efficacy of immunotherapy needs further research.

5,407 views

27 citations

ORIGINAL RESEARCH
21 January 2022
Gemcitabine-Resistant Biomarkers in Bladder Cancer are Associated with Tumor-Immune Microenvironment
Yuxuan Song, 7 more and Tao Xu

9 Authors

6,440 views

21 citations

ORIGINAL RESEARCH
24 December 2021
LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients
Xiaonan Zheng, 8 more and Qiang Wei

10 Authors

4,875 views

13 citations

ORIGINAL RESEARCH
3 December 2021
DNA Methylation Modification Map to Predict Tumor Molecular Subtypes and Efficacy of Immunotherapy in Bladder Cancer
Fangdie Ye, 7 more and Haowen Jiang

9 Authors

3,586 views

25 citations

ORIGINAL RESEARCH
3 December 2021
Multi-Omics Analysis of Novel Signature for Immunotherapy Response and Tumor Microenvironment Regulation Patterns in Urothelial Cancer
Guangdi Chu, 3 more and Haitao Niu

5 Authors

3,915 views

12 citations

ID2 Inhibits Bladder Cancer Progression and Metastasis via PI3K/AKT Signaling Pathway
ORIGINAL RESEARCH
22 October 2021
ID2 Inhibits Bladder Cancer Progression and Metastasis via PI3K/AKT Signaling Pathway
Weipu Mao, 5 more and Ming Luo

7 Authors

Background: Inhibitors of DNA-binding (ID) proteins are important regulators of cell proliferation and differentiation. The aim of this study was to evaluated the role of ID proteins in bladder cancer (BCa) and related molecular mechanisms. Methods: The TCGA database was analyzed for the expression and clinical significance of ID proteins. The expression of ID2 was determined by qRT-PCR, immunohistochemical staining and western blot. The role of ID2 was determined by CCK-8, colony formation, wound healing, transwell and xenograft tumor assays, and the potential mechanism of ID2 in BCa was investigated by RNA sequencing. Results: ID2 expression was significantly downregulated in TCGA database and clinical samples, and high ID2 expression was associated with low-grade tumor staging and correlated with better overall survival, disease specific survival and progress free interval. In vivo and in vitro experiments showed that knockdown of ID2 promoted proliferation, migration, invasion and metastasis of BCa cells, while overexpression of ID2 significantly inhibited cell proliferation, migration, invasion and metastasis. Mechanistically, ID2 acts as a tumor suppressor through PI3K/AKT signaling pathway to inhibit the progression and metastasis of BCa. Conclusions: Our results suggest that ID2 exerts tumor suppressive effects in BCa through PI3K/AKT signaling pathway, and altered ID2 expression can be used as a biomarker of BCa progression and metastasis.

4,876 views

28 citations

ORIGINAL RESEARCH
16 September 2021
BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-κB Signaling Pathway Through Targeting TRAF2
Huangheng Tao, 7 more and Tao Liu

9 Authors

4,990 views

26 citations

ORIGINAL RESEARCH
31 August 2021
Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer
Mengjia Huang, 10 more and Fangrong Yan

12 Authors

Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Bladder Cancer
Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic biomarker and predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients' clinical response to immunotherapy and promoting individualized tumor immunotherapy in the future.

4,736 views

22 citations

ORIGINAL RESEARCH
11 March 2021
Immune Profiling Reveals Molecular Classification and Characteristic in Urothelial Bladder Cancer
Li Yang, 9 more and Yi Zhang

11 Authors

4,015 views

10 citations