A review on the role of M2 macrophages in bladder cancer; pathophysiology and targeting

Sharifi, Laleh; Nowroozi, Mohammad Reza; Amini, Erfan; Kourosh-Arami, Masoumeh; Ayati, Mohsen; Mohsenzadegan, Monireh

doi:10.1016/j.intimp.2019.105880

Cited by 71 publications

(38 citation statements)

References 149 publications

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“…Besides, we investigated whether this index is related to immune cell infiltration, and found that higher infiltrating percentage of macrophages M0, macrophages M2 and neutrophils were significantly associated with the poor prognosis of BCa, while lower infiltrating percentage of T cells CD8, T cells CD4 memory activated or T cells follicular helper were significantly associated with the poor prognosis of BCa. It is reported that M2 macrophages play a vital role in immune responses induced by BCG against BCa [30]. Qiu et al [31] demonstrated the regulation role of tumor-associated macrophages in BCa cell growth.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis

Lin

et al. 2020

Cancer Cell Int

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Background: Bladder cancer (BCa) is one of the important tumors that have been proven to be treatable with immunotherapy. This study aims to identify and validate a molecular prognostic index of BCa based on immunogenomic landscape analysis. Methods: The cancer genome atlas (TCGA) database and immunology database and analysis portal (ImmPort) database were used to identified differentially expressed immune-related genes (IRGs). Prognostic IRGs were screened and protein-protein interaction (PPI) network was constructed. Multivariate Cox analysis was performed to develop a molecular prognostic index of BCa. Internal and external validation were then performed in TCGA cohort and GEO cohort, respectively. Besides, we also explore the relationship between this index and clinical characteristics, immune cell infiltration and tumor microenvironment. Results: A total of 61 prognostic IRGs were identified and a molecular prognostic index was developed. The top four hub genes included MMP9, IGF1, CXCL12 and PGF. The difference in overall survival between high-risk group and low-risk group was statistically significant. The area under curve of the receiver operating characteristic (ROC) curve was 0.757, suggesting the potential for this index. Besides, Internal validation using TCGA cohort and external validation using GEO cohort indicated that this index was of great performance in predicting outcome. T cells CD8, T cells CD4 memory activated, T cells follicular helper, macrophages M0, macrophages M2 and neutrophils were significantly associated with prognosis of BCa patients. Female, high grade, stage III&IV, N1-3 and T3-4 were associated significantly with higher risk score compared with male, low grade, stage I&II, N0 and T1-2, respectively. High risk score had a positive association with higher stromal score and ESTIMATE score while high risk score had a negative association with tumor purity. Conclusions: This study identified several prognostic immune-related genes of clinical value. Besides, we developed and validated a molecular index based on immunogenomic landscape analysis, which performed well in predicting prognosis of BCa. Further researches are needed to verify the effectiveness of this index and these vital genes.

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Section: Discussionmentioning

confidence: 99%

Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis

Lin

et al. 2020

Cancer Cell Int

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“…M2-like TAMs can in turn accelerate tumour growth, promote metastasis, and inhibit immune killing to promote tumour progression [ 45 ]. High TAM infiltration is correlated with poor clinical outcomes and decreases responses to standard-of-care therapeutics in BCa [ 22 , 46 ]. We demonstrated that in BCa cells, KDM6A inhibits the recruitment of macrophages and the expression of IL-6 and CCL2, which are important for TAM recruitment [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

et al. 2021

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Background KDM6A, a histone demethylase, is frequently mutated in bladder cancer (BCa). However, the role and detailed molecular mechanism of KDM6A involved in bladder cancer progression remains unknown. Methods Tissue specimens were used to determine the expression levels and prognostic values of KDM6A and ARHGDIB. The MTT, colony formation, wound healing and Transwell migration and invasion assays were employed to detect the BCa cell proliferation, migration and invasion, respectively. Chemotaxis of macrophages was used to evaluate the ability of KDM6A to recruit macrophages. A subcutaneous tumour model and tail vein tumour injection in nude mice were used to assess the role of KDM6A in vivo. RNA sequencing, qPCR, Western blot, ChIP and phalloidin staining assay were performed to investigate the molecular functions of KDM6A. Dual-luciferase reporter assay was used to determine the effects of KDM6A and FOXA1 on the promoters of the ARHGDIB and KDM6A. Results We showed that the KDM6A inhibited the motility and invasiveness of the BCa cells. Mechanistically, KDM6A promotes the transcription of ARHGDIB by demethylating histone H3 lysine di/trimethylation (H3K27me2/3) and consequently leads to inhibition of Rac1. EZH2, which catalyses the methylation of H3K27, functions to silence ARHGDIB expression, and an EZH2 inhibitor can neutralize the metastatic effect caused by KDM6A deficiency. Furthermore, we demonstrated that FOXA1 directly binds to the KDM6A promoter and thus transactivates KDM6A, leading to diminished metastatic potential. Conclusion Our findings establish the critical role of the FOXA1-KDM6A-ARHGDIB axis in restraining the malignancy of BCa and identify KDM6A and EZH2 as potential therapeutic targets in the management of BCa.

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“…Tumor-associated macrophages are part of the tumor microenvironmental cells and affect the progress of solid tumors. Studies have found that macrophages can directly affect the immune response to bladder cancer induced by Bacillus Calmette-Guerin [ 38 ]. In addition, studies have found that exosomes miR-21 can promote cancer progression through polarized tumor-associated macrophages [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Development of a prognostic index and screening of prognosis related genes based on an immunogenomic landscape analysis of bladder cancer

Liu

Yang

et al. 2021

Aging

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Background: Bladder cancer (BLCA) is one of the most common urinary tract malignant tumors. It is associated with poor outcomes, and its etiology and pathogenesis are not fully understood. There is great hope for immunotherapy in treating many malignant tumors; therefore, it is worthwhile to explore the use of immunotherapy for BLCA.Methods: Gene expression profiles and clinical information were obtained from The Cancer Genome Atlas (TCGA), and immune-related genes (IRGs) were downloaded from the Immunology Database and Analysis Portal. Differentially-expressed and survival-associated IRGs in patients with BLCA were identified using computational algorithms and Cox regression analysis. We also performed functional enrichment analysis. Based on IRGs, we employed multivariate Cox analysis to develop a new prognostic index.Results: We identified 261 IRGs that were differentially expressed between BLCA tissue and adjacent tissue, 30 of which were significantly associated with the overall survival (all P<0.01). According to multivariate Cox analysis, nine survival-related IRGs (MMP9, PDGFRA, AHNAK, OAS1, OLR1, RAC3, IGF1, PGF, and SH3BP2) were high-risk genes. We developed a prognostic index based on these IRGs and found it accurately predicted BLCA outcomes associated with the TNM stage. Intriguingly, the IRG-based prognostic index reflected infiltration of macrophages.Conclusions: An independent IRG-based prognostic index provides a practical approach for assessing patients' immune status and prognosis with BLCA. This index independently predicted outcomes of BLCA.

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A review on the role of M2 macrophages in bladder cancer; pathophysiology and targeting

Cited by 71 publications

References 149 publications

Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis

Development and validation of a molecular prognostic index of bladder cancer based on immunogenomic landscape analysis

KDM6A-ARHGDIB axis blocks metastasis of bladder cancer by inhibiting Rac1

Development of a prognostic index and screening of prognosis related genes based on an immunogenomic landscape analysis of bladder cancer

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