Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression

Abstract Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have witnessed significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage BLCA at advanced stages when platinum-based therap...

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Autores principales:	YiHeng Du, Jin Cao, Xiang Jiang, XiaoWei Cai, Bo Wang, Yi Wang, XiZhi Wang, BoXin Xue
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Bladder cancer CXCL12 Cancer-associated fibroblasts Carcinogenesis Immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/e86b7ab01d4643d4b570110976f66586
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spelling	oai:doaj.org-article:e86b7ab01d4643d4b570110976f665862021-11-21T12:39:35ZComprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression10.1186/s12935-021-02314-y1475-2867https://doaj.org/article/e86b7ab01d4643d4b570110976f665862021-11-01T00:00:00Zhttps://doi.org/10.1186/s12935-021-02314-yhttps://doaj.org/toc/1475-2867Abstract Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have witnessed significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage BLCA at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) is essential in impacting BLCA patients' prognosis and responsiveness to ICB therapy. CXCL12 is a stromal secreted factor that was essentially involved in regulating the TME among cancers. In this article, we thoroughly investigated the TME regulating roles of CXCL12 in BLCA and revealed its critical involvement in the development of BLCA, which was closely correlated with inflammatory fibroblasts (iCAFs). Methods We examined the gene expression profiles in the TCGA and GEO database to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of BLCA. The receiver operating characteristic curve was used to explore the accuracy of CXCL12 along with multiple iCAFs-associated genes in the diagnosis of BLCA. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. The "maftool" R package analyzed the oncogenic mutations in BLCA patients. Bioinformatics analysis results were further validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors. Results This manuscript revealed a significantly reduced expression of CXCL12 in BLCA compared with normal tissue. The expressions of various marker genes for iCAFs were also reduced considerably in BLCA tissues, highlighting the reduction of iCAFs in the pathogenesis of BLCA. Further studies revealed that CXCL12 and iCAFs were associated with pathological features, TME remodeling and aging in BLCA patients. The iCAFs signature further confirmed the intricate immunomodulatory roles of iCAFs in BLCA. Gene mutation analysis revealed the essential relationship between iCAFs and the mutation frequency of oncogenic genes, including TP53 and FGFR3. Meantimes, iCAFs levels also significantly affected BLCA patients' mutations in the TP53 and RTK-RAS pathways. Finally, our results confirmed the significant exclusion of CD8 + T cells by iCAFs, which further influenced the immunotherapy responsiveness in BLCA patients. Conclusions This article highlighted the impact of CXCL12 on the pathogenesis and progression of BLCA. The reduced expression levels of iCAFs markers, including CXCL12, were highly accurate in the diagnosis of BLCA, suggesting the reduction of iCAFs accompanied bladder carcinogenesis. However, both CXCL12 and iCAFs significantly impacted the prognosis and immunotherapy responsiveness for BLCA patients by remodeling the TME. Our results critically suggested the dual roles of iCAFs in the carcinogenesis and progression of BLCA. Further exploration of iCAFs might unravel potential diagnostic biomarkers and therapeutic targets for BLCA.YiHeng DuJin CaoXiang JiangXiaoWei CaiBo WangYi WangXiZhi WangBoXin XueBMCarticleBladder cancerCXCL12Cancer-associated fibroblastsCarcinogenesisImmunotherapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCancer Cell International, Vol 21, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Bladder cancer CXCL12 Cancer-associated fibroblasts Carcinogenesis Immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Bladder cancer CXCL12 Cancer-associated fibroblasts Carcinogenesis Immunotherapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 YiHeng Du Jin Cao Xiang Jiang XiaoWei Cai Bo Wang Yi Wang XiZhi Wang BoXin Xue Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
description	Abstract Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have witnessed significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage BLCA at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) is essential in impacting BLCA patients' prognosis and responsiveness to ICB therapy. CXCL12 is a stromal secreted factor that was essentially involved in regulating the TME among cancers. In this article, we thoroughly investigated the TME regulating roles of CXCL12 in BLCA and revealed its critical involvement in the development of BLCA, which was closely correlated with inflammatory fibroblasts (iCAFs). Methods We examined the gene expression profiles in the TCGA and GEO database to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of BLCA. The receiver operating characteristic curve was used to explore the accuracy of CXCL12 along with multiple iCAFs-associated genes in the diagnosis of BLCA. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. The "maftool" R package analyzed the oncogenic mutations in BLCA patients. Bioinformatics analysis results were further validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors. Results This manuscript revealed a significantly reduced expression of CXCL12 in BLCA compared with normal tissue. The expressions of various marker genes for iCAFs were also reduced considerably in BLCA tissues, highlighting the reduction of iCAFs in the pathogenesis of BLCA. Further studies revealed that CXCL12 and iCAFs were associated with pathological features, TME remodeling and aging in BLCA patients. The iCAFs signature further confirmed the intricate immunomodulatory roles of iCAFs in BLCA. Gene mutation analysis revealed the essential relationship between iCAFs and the mutation frequency of oncogenic genes, including TP53 and FGFR3. Meantimes, iCAFs levels also significantly affected BLCA patients' mutations in the TP53 and RTK-RAS pathways. Finally, our results confirmed the significant exclusion of CD8 + T cells by iCAFs, which further influenced the immunotherapy responsiveness in BLCA patients. Conclusions This article highlighted the impact of CXCL12 on the pathogenesis and progression of BLCA. The reduced expression levels of iCAFs markers, including CXCL12, were highly accurate in the diagnosis of BLCA, suggesting the reduction of iCAFs accompanied bladder carcinogenesis. However, both CXCL12 and iCAFs significantly impacted the prognosis and immunotherapy responsiveness for BLCA patients by remodeling the TME. Our results critically suggested the dual roles of iCAFs in the carcinogenesis and progression of BLCA. Further exploration of iCAFs might unravel potential diagnostic biomarkers and therapeutic targets for BLCA.
format	article
author	YiHeng Du Jin Cao Xiang Jiang XiaoWei Cai Bo Wang Yi Wang XiZhi Wang BoXin Xue
author_facet	YiHeng Du Jin Cao Xiang Jiang XiaoWei Cai Bo Wang Yi Wang XiZhi Wang BoXin Xue
author_sort	YiHeng Du
title	Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
title_short	Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
title_full	Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
title_fullStr	Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
title_full_unstemmed	Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
title_sort	comprehensive analysis of cxcl12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression
publisher	BMC
publishDate	2021
url	https://doaj.org/article/e86b7ab01d4643d4b570110976f66586
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Comprehensive analysis of CXCL12 expression reveals the significance of inflammatory fibroblasts in bladder cancer carcinogenesis and progression

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