Wnt/β-Catenin Signaling and Immunotherapy Resistance: Lessons for the Treatment of Urothelial Carcinoma

Chehrazi‐Raffle, Alex; Dorff, Tanya B.; Pal, Sumanta K.; Lyou, Yung

doi:10.3390/cancers13040889

Cited by 27 publications

(25 citation statements)

References 74 publications

(154 reference statements)

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“…Therefore, it is plausible to hypothesize that some patients harbor genetic events that confer resistance to ICIs. In this regard, aberrant activation of Wnt/β-catenin has emerged as an important pathway mediating ICI resistance (138,139). Harding et al reported that in HCC patients treated with ICIs, activation of the Wnt/β-catenin pathway correlates with lower disease control rate and lower progression-free and overall survival rates (140).…”

Section: Targeting Wnt/β-catenin For Hcc Treatmentmentioning

confidence: 99%

β-Catenin signaling in hepatocellular carcinoma

Xu¹,

Xu²,

Zhang³

et al. 2022

Journal of Clinical Investigation

143

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Section: Targeting Wnt/β-catenin For Hcc Treatmentmentioning

confidence: 99%

β-Catenin signaling in hepatocellular carcinoma

Xu¹,

Xu²,

Zhang³

et al. 2022

Journal of Clinical Investigation

143

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“…Furthermore, a study of polymorphisms in 40 genes of the Wnt/β-catenin signaling pathway has suggested that variants may play a role in the etiology of bladder cancer [ 9 ]. With regard to therapy resistance, it has recently been documented that the Wnt/β-catenin pathway may be involved in resistance to cisplatin [ 10 ], doxorubicin [ 11 , 12 ], and immunotherapy [ 13 ] in bladder cancer. To our knowledge, its role in the acquisition of paclitaxel or docetaxel resistance has not been described.…”

Section: Introductionmentioning

confidence: 99%

Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties

Jiménez-Guerrero

Belmonte-Fernández

Flores

et al. 2021

IJMS

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The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder cancer. Here, our goal was to analyze the role of the Wnt/β-catenin pathway in paclitaxel resistance and to study the therapeutic efficacy of its inhibition in bladder cancer cells, as well as to determine its influence in the maintenance of the CSC-like phenotype in bladder cancer. Our results show that paclitaxel-resistant HT1197 cells have hyperactivation of the Wnt/β-catenin pathway and increased CSC-like properties compared with paclitaxel-sensitive 5637 cells. Paclitaxel sensitivity diminishes in 5637 cells after β-catenin overexpression or when they are grown as tumorspheres, enriched for the CSC-like phenotype. Additionally, downregulation of β-catenin or inhibition with XAV939 sensitizes HT1197 cells to paclitaxel. Moreover, a subset of muscle-invasive bladder carcinomas shows aberrant expression of β-catenin that associates with positive expression of the CSC marker ALDH1A1. In conclusion, we demonstrate that Wnt/β-catenin signaling contributes to paclitaxel resistance in bladder cancer cells with CSC-like properties.

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“…Accordingly, these observations suggest that SFRP2, a putative Wnt inhibitor, may function at the interactions between tumor cells and fibroblasts in UC development. Nevertheless, the Wnt/β-catenin signaling has also been suggested to drive cytotoxic T cell exclusion by modulating the crosstalk between tumor cells and tumor-associated macrophages (TAMs) and lead to immunotherapy resistance in UC treatment ( 12 ). These further highlight the complexity of the TME that creates a favorable niche to reduce treatment efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…However, accumulated investigations have shown incompatible evidence between the Wnt/β-catenin signaling and UC carcinogenesis ( 10 , 11 ). Additionally, the aberrant Wnt/β-catenin signaling is not only restricted to cancer cells but also implicated in dynamic interactions with the tumor microenvironment (TME) and immune system in UC ( 12 ). These observations further emphasize the molecular heterogeneity of UC, and a deeper understanding of the molecular characterization of UC may come up with more hints for how such pathways be therapeutically targeted.…”

Section: Introductionmentioning

confidence: 99%

High Stromal SFRP2 Expression in Urothelial Carcinoma Confers an Unfavorable Prognosis

Lai

Chiu²,

Kuo

et al. 2022

Front. Oncol.

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BackgroundUrothelial carcinoma (UC) patients often bear clinical and genetic heterogeneity, which may differ in management and prognosis. Especially, patients with advanced/metastatic UC generally have a poor prognosis and survive for only few months. The Wnt/β-catenin signaling is found to be highly activated in several cancers, including UC. However, accumulated evidence has shown discordance between the Wnt/β-catenin signaling and UC carcinogenesis. Accordingly, we aim to get a better understanding of the molecular characterization of UC, focusing on the Wnt signaling, which may add value to guiding management more precisely.Patients and MethodsClinical data and pathological features were retrospectively surveyed. The correlations of secreted Frizzled-related protein 2 (SFRP2) immunoexpression with clinicopathological features were analyzed by Pearson’s chi-square test. The Kaplan–Meier method with a log-rank test was employed to plot survival curves. All significant features from the univariate analysis were incorporated into the Cox regression model for multivariate analysis.ResultsFollowing data mining on a transcriptome dataset (GSE31684), we identified that 8 transcripts in relation to the Wnt signaling pathway (GO: 0016055) were significantly upregulated in advanced/metastatic bladder tumors. Among these transcripts, the SFRP2 level showed the most significant upregulation. Additionally, as SFRP2 is a putative Wnt inhibitor and may be expressed by stroma, we were interested in examining the immunoexpression and clinical relevance of stromal and tumoral SFRP2 in our urothelial carcinoma cohorts containing 295 urinary bladder UC (UBUC) and 340 upper urinary tract UC (UTUC) patients. We observed that high SFRP2 expression in stroma but not in tumors is significantly linked to aggressive UC features, including high tumor stage and histological grade, positive nodal metastasis, the presence of vascular and perineural invasion, and high mitotic activity in UBUC and UTUC. Moreover, high stromal SFRP2 expression significantly and independently predicted worse clinical outcomes in UBUC and UTUC. Utilizing bioinformatic analysis, we further noticed that stromal SFRP2 may link epithelial–mesenchymal transition (EMT) to UC progression.ConclusionCollectively, these results imply that stromal SFRP2 may exert oncogenic function beyond its Wnt antagonistic ability, and stromal SFRP2 expression can provide prognostic and therapeutic implications for UC patients.

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Wnt/β-Catenin Signaling and Immunotherapy Resistance: Lessons for the Treatment of Urothelial Carcinoma

Cited by 27 publications

References 74 publications

β-Catenin signaling in hepatocellular carcinoma

β-Catenin signaling in hepatocellular carcinoma

Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties

High Stromal SFRP2 Expression in Urothelial Carcinoma Confers an Unfavorable Prognosis

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