Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer

Stojnev, Slavica; Kokoris, Jovana Čukuranović; Conic, Irena; Petković, Ivan; Ilić, Sonja; Milosević-Stevanović, Jelena; Veličković, Ljubinka Janković

doi:10.3390/medicina55060302

Cited by 18 publications

(17 citation statements)

References 31 publications

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“… 71 72 It is also a key inducer and regulator of EMT, an essential process for cancer progression and metastatic spread. 53 73 TGF-β expression is an independent predictor of outcomes in urothelial cancer, 74 but this association had not been demonstrated thus far in gastric cancer. Our study demonstrated that a high TGF-β fibrosis gene signature is negatively associated with survival in gastric cancer.…”

Section: Discussionmentioning

confidence: 97%

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival

Shah

Cunningham

Metges

et al. 2021

J Immunother Cancer

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BackgroundMatrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer.MethodsPhase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers.Results144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (<1 year) survivors showed that GRB7 was associated with survival beyond 1 year. Human epidermal growth factor receptor 2 (HER2)-positive disease was associated with significantly longer survival (p=0.0077). Median tumor mutation burden (TMB) was 2.01; patients with TMB ≥median had longer survival (p=0.0025) and improved PFS (p=0.016). Based on a model accounting for TMB, TGF-β fibrosis, and HER2, TMB was the main driver of survival in this patient population.ConclusionCombination of ADX+NIVO had a favorable safety profile but did not improve efficacy compared with NIVO alone in patients with pretreated metastatic gastric or GEJ adenocarcinoma. HER2 positivity, higher TMB or GRB7, and lower TGF-β were associated with improved outcomes.Trial registration numberNCT02864381 or GS-US-296–-2013.

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Section: Discussionmentioning

confidence: 97%

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival

Shah

Cunningham

Metges

et al. 2021

J Immunother Cancer

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“…Several studies focusing on the prognostic prediction of TGF-b have been published. Slavica Stojnev et al evaluated the associations of TGF-b1, Smad4, and Smad2 with clinicopathologic characteristics and prognosis in urothelial bladder cancer (25). We compared our work with these previous works.…”

Section: Discussionmentioning

confidence: 99%

“…The construction and validation of scoring models has been a core of ceaseless studies in oncology research. Numerous risk models related to EMT, immune TME, and hypoxia have been lucubrated and reported with the potential to predict prognosis and guide precision medicine for BLCA (23,25,(65)(66)(67)(68). It was remarkable that our previous work clarified thought in screening key genes, constructing a gene model, associating the model with immune characteristics, and evaluating the accuracy for predicting prognosis and treatment response.…”

Section: Discussionmentioning

confidence: 99%

“…With the improvement of genomic sequencing methods, more and more genomic signatures have been created to predict the prognosis and therapeutic opportunities for cancers (8,23,24). In BLCA, Stojnev et al explored the roles of three key components (TGF-b1, Smad2, and Smad4) of the canonical TGFb pathway in predicting the prognosis (25). However, few studies have been conducted to systematically correlate the TGF-b signature with the tumour microenvironment phenotypes for BLCA.…”

Section: Introductionmentioning

confidence: 99%

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A Novel TGF-β Risk Score Predicts the Clinical Outcomes and Tumour Microenvironment Phenotypes in Bladder Cancer

Liu

et al. 2021

Front. Immunol.

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BackgroundThe TGF-β pathway plays critical roles in numerous malignancies. Nevertheless, its potential role in prognosis prediction and regulating tumour microenvironment (TME) characteristics require further elucidation in bladder cancer (BLCA).MethodsTGF-β-related genes were comprehensively summarized from several databases. The TCGA-BLCA cohort (training cohort) was downloaded from the Cancer Genome Atlas, and the independent validation cohorts were gathered from Xiangya Hospital (Xinagya cohort) and Gene Expression Omnibus. Initially, we identified differentially expressed TGF-β genes (DEGs) between cancer and normal tissues. Subsequently, univariate Cox analysis was applied to identify prognostic DEGs, which were further used to develop the TGF-β risk score by performing LASSO and multivariate Cox analyses. Then, we studied the role of the TGF-β risk score in predicting prognosis and the TME phenotypes. In addition, the role of the TGF-β risk score in guiding precision treatments for BLCA has also been assessed.ResultsWe successfully constructed a TGF-β risk score with an independent prognostic prediction value. A high TGF-β risk score indicated an inflamed TME, which was supported by the positive relationships between the risk score, enrichment scores of anticancer immunity steps, and the infiltration levels of tumour-infiltrating immune cells. In addition, the risk score positively correlated with the expression of several immune checkpoints and the T cell inflamed score. Consistently, the risk score was positively related to the enrichment scores of most immunotherapy-positive pathways. In addition, the sensitivities of six common chemotherapeutic drugs were positively associated with the risk score. Furthermore, higher risk score indicated higher sensitivity to radiotherapy and EGFR-targeted therapy. On the contrary, patients with low-risk scores were more sensitive to targeted therapies, including the blockade of FGFR3 and WNT-β-catenin networks.ConclusionsWe first constructed and validated a TGF-β signature that could predict the prognosis and TME phenotypes for BLCA. More importantly, the TGF-β risk score could aid in individual precision treatment for BLCA.

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“…The tumors with high TLR4 expression have low infiltrated levels of plasma cells, M0 macrophages, and M1 macrophages with activated TGF-β and apoptosis pathways. High expression of Smad2 and Smad4 in the TGF-β signaling pathway predicts longer OS in bladder cancer patients, while TGF-β1 is inversely correlated with the survival rate (Stojnev et al, 2019). BCG can stimulate TLR2/4 in bladder tumor cells to decrease cell proliferation and up-regulate apoptosis (Camargo et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

Xia

Sun

et al. 2021

Front. Cell Dev. Biol.

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BackgroundThe toll-like receptor 4 (TLR4) agonist, Bacille Calmette-Guérin, has exhibited gratifying effects in treating bladder cancer. The study aims to explore the expression pattern, prognostic value, and potential mechanism of TLR4 in bladder cancer.MethodsThe transcriptome file from the GSE13507 dataset in the Gene Expression Omnibus database and the promoter methylation file from the bladder cancer dataset in The Cancer Genome Atlas database were downloaded for analysis. The prognostic value of the TLRs was assessed by univariate Cox regression. Immunohistochemistry was applied to verify the expression of TLR4 in bladder cancer. The drug response is estimated through the R package “pRRophetic.” The CIBERSORT algorithm was carried out to estimate the infiltrating immune cells of samples. Gene Set Enrichment Analysis (GSEA) was performed to identify the pathways involved under varied TLR4 expression levels.ResultsTLR4 is decreased in tumor tissues compared with surrounding tumor tissues or normal tissue, which is also positively correlated to the overall survival rate (hazard ratio [HR] = 0.38) and cancer-specific survival rate (HR = 0.15) of patients with bladder cancer. Low expression of TLR4 is observed in tumors with malignant performance (high pathological grade, higher tumor stage, and progression). Patients with low TLR4 levels are more sensitive to gemcitabine rather than cisplatin. The promoter methylation level of TLR4 is positively associated with TLR4 expression (P < 0.001). The cg14629571 methylation site largely contributes to the overall methylation level. The CIBERSORT analysis shows that high TLR4 expression is associated with lower levels of plasma cells, M0 macrophages, and M1 macrophages. The GSEA results indicate that the TGF-β pathway and apoptosis are activated in high TLR4 bladder cancer, while G2M checkpoint and E2F targets pathways are enriched in low TLR4 bladder cancer.ConclusionThis research discusses the abnormal expression and prognostic value of TLR4 in bladder cancer. The TLR4 expression can effectively predict oncological outcomes and drug sensitivity of bladder cancer patients. TLR4 is also associated with infiltrating immune cell variation and cancer pathway dysregulation. The results provide a novel prognostic marker and potential drug targets for bladder cancer.

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Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer

Cited by 18 publications

References 31 publications

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival

Randomized, open-label, phase 2 study of andecaliximab plus nivolumab versus nivolumab alone in advanced gastric cancer identifies biomarkers associated with survival

A Novel TGF-β Risk Score Predicts the Clinical Outcomes and Tumour Microenvironment Phenotypes in Bladder Cancer

Toll-Like Receptor 4 as a Favorable Prognostic Marker in Bladder Cancer: A Multi-Omics Analysis

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