Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells.
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ABSTRACT:
SUBMITTER: Chan KS
PROVIDER: S-EPMC2720852 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cuproptosis is a kind of cell death dependent on copper. We aimed to explore the functions of the cuproptosis in the tumor microenvironment (TME) and construct a cuproptosis-related prognosis signature in bladder cancer (BCa). Using BCa patients in the public cohort, the cuproptosis-related molecular subtypes and cuproptosis-related prognosis signature were developed. Three cuproptosis-related molecular subtypes, with different prognoses and TME characteristics, were identified in BCa. The cuproptosis-related prognosis signature can divide patients into high- and low-risk groups with different prognoses, TME characteristics, chemotherapeutic drug susceptibility and immunotherapeutic response. Low risk group patients had a favored prognosis and response to immunotherapy. The dysregulation of cuproptosis-related genes expression levels was validated in multiple BCa cells using in vitro experiments. Cuproptosis has an important role in the tumor progression and the characterization of TME in BCa. The cuproptosis-related prognosis signature is a useful biomarker that can reflect the prognosis, TME characteristics, immunotherapeutic response and chemotherapeutic drug susceptibility in BCa patients.
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Project description:MicroRNAs play an important role in the pathogenesis of different types of cancer including bladder cancer. MiR-21 has been identified to have an oncogenic function, while its inhibition suppresses tumor growth. Here, we followed an integrated bioinformatics and molecular analyses to identify the molecular mediators of miR-21 oncogenic function in bladder cancer and evaluate the therapeutic potential of a chemically-modified miR-21 inhibitor in bladder xenografts. MiR-21 expression was found to up-regulated in human bladder cancers relative to normal tissues and miR-21 inhibition suppressed bladder cancer cell properties, including growth, invasiveness and anchorage-independence. Intravenous administration of an antisense oligonucleotide against miR-21 harboring locked-nucleic-acid (LNA-miR-21) modifications blocked bladder tumor growth in vivo. Transcriptomic analysis of 28 bladder cancer cell lines revealed a gene signature that negatively correlated with miR-21 expression levels. Bioinformatics and 3’UTR luciferase assay analyses revealed a direct interaction between miR-21 the 3’UTR of PPP2R2A gene. Inhibition of PPP2R2A expression induced bladder cancer growth, suggesting its tumor suppressor function. Gene profiling followed by IPA network analysis revealed that PPP2R2A regulates the ERK1/2 molecular network. Taken together, PPP2R2A is the functional mediator of miR-21 oncogenic activity on bladder cancer and LNA-miR-21 could have a therapeutic potential in bladder cancer patients.
2018-04-19 | GSE97782 | GEO
Project description:BackgroundTreatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant.MethodsGene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group.ResultsCD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo.ConclusionOur studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy.
| S-EPMC7225664 | biostudies-literature
Project description:BackgroundSUMOylation is an important component of post-translational protein modifications (PTMs), and bladder cancer (BCa) is the ninth most common cancer around the world. But the comprehensive role of SUMOylation in shaping tumor microenvironment (TME) and influencing tumor clinicopathological features and also the prognosis of patients remains unclear.MethodsUsing the data downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), we comprehensively evaluated the SUMOylation patterns of 570 bladder cancer samples, and systematically correlated these SUMOylation patterns with TME immune cell infiltrating characteristics. The SUMO score was constructed to quantify SUMOylation patterns of individuals using principal component analysis (PCA) algorithms.ResultsTwo distinct SUMOylation patterns and gene clusters were finally determined. Significant differences in the prognosis of patients were found among two different SUMOylation 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 named SUMO score to quantify the SUMOylation pattern of individuals with BCa, which was discovered to be tightly connected with tumor clinicopathological characteristics and could predict the prognosis of patients with BCa. Moreover, SUMO score was a considerable predictive indicator for the survival outcome independent of tumor mutation burden (TMB) and low SUMO score was related to better response to immunotherapy using PD-1 blockade. We also found that there existed a significant relationship between sensitivity to commonly used chemotherapy drugs and SUMO score. Finally, a nomograph based on five features, namely, SUMO score, age, gender, T category, and M category was constructed to predict the survival probability of patients with BCa in 1, 3, and 5 years, respectively.ConclusionsOur work demonstrated and overviewed the complicated regulation mechanisms of SUMOylation in bladder cancer, and better understanding and evaluating SUMOylation patterns could be helpful in guiding clinical therapeutic strategy and improving the prognosis of patients with BCa.
| S-EPMC8995476 | biostudies-literature
Project description:Primary human squamous cell carcinomas (SCCas) are heterogeneous invasive tumors with proliferating outer layers and inner differentiating cell masses. To determine if tumor-initiating cells (TICs) are present in SCCas, we utilized newly developed reliable in vitro and in vivo xenograft assays that propagate human SCCas, and demonstrated that a small subset of SCCa cells (∼1%) expressing Prominin-1 (CD133) in the outer layers of SCCas were highly enriched for TICs (∼1/400) compared with unsorted SCCa cells (TICs ∼1/10(6)). Xenografts of CD133+ SCCas recreated the original SCCa tumor histology and organizational hierarchy, whereas CD133- cells did not, and only CD133+ cells demonstrated the capacity for self-renewal in serial transplantation studies. We present a model of human SCCas in which tumor projections expand with outer leading edges that contain CD133+ TICs. Successful cancer treatment will likely require that the TICs identified in cancers be targeted therapeutically. The demonstration that TICs are present in SCCas and are enriched in a CD133- expressing subpopulation has not been, to our knowledge, previously reported.
| S-EPMC3258300 | biostudies-literature
Project description:Tumor-initiating cells (TICs) have been shown both experimentally and clinically to be resistant to radiation and chemotherapy, potentially resulting in residual disease that can lead to recurrence. In this study, we demonstrate that TICs isolated from p53 null mouse mammary tumors repair DNA damage following in vivo ionizing radiation more efficiently than the bulk of the tumor cells. Down-regulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was observed both in fluorescence activated cell sorting (FACS)-isolated TICs as compared to non-TICs and in TIC-enriched mammospheres as compared to primary tumor cells depleted of TICs. This effect was accompanied by increased Akt signaling, as well as by the direct activation of the canonical Wnt/beta-catenin signaling pathway specifically within the TIC subpopulation by phosphorylation of beta-catenin on serine 552. Using limiting dilution transplantation performed on p53 null tumor cells transduced with Wnt reporter lentivirus, we demonstrated that FACS sorting of cells expressing TOP-eGFP resulted in a marked enrichment for TICs. Furthermore, FACS analysis demonstrated that cells with active Wnt signaling overlapped with the TIC subpopulation characterized previously using cell surface markers. Finally, pharmacological inhibition of the Akt pathway in both mammospheres and syngeneic mice bearing tumors was shown to inhibit canonical Wnt signaling as well as the repair of DNA damage selectively in TICs, sensitizing them to ionizing radiation treatment. Thus, these results suggest that pretreatment with Akt inhibitors before ionizing radiation treatment may be of potential therapeutic benefit to patients.
| S-EPMC2840501 | biostudies-literature
Project description:Human leukocyte antigen class I (HLA-I) down-regulation has been reported in many human cancers to be associated with poor clinical outcome. However, its connection to tumor-initiating cells (TICs) remains unknown. In this study, we report that HLA-I is down-regulated in a subpopulation of cells that have high tumor initiating capacity in different types of human sarcomas. Detailed characterization revealed their distinct molecular profiles regarding proliferation, apoptosis and stemness programs. Notably, these TICs can be induced to differentiate along distinct mesenchymal lineages, including the osteogenic pathway. The retinoic acid receptor signaling pathway is overexpressed in HLA-1 negative TICs. All-trans retinoic acid treatment successfully induced osteogenic differentiation of this subpopulation, in vitro and in vivo, resulting in significantly decreased tumor formation. Thus, our findings indicate down-regulated HLA-I is a shared feature of TICs in a variety of human sarcomas, and differentiation therapy strategies may specifically target undifferentiated TICs and inhibit tumor formation.
| S-EPMC5988213 | biostudies-literature
Project description:Background: Tumor necrosis factor (TNF) family members play vital roles in cancer development and antitumor 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; another two Gene Expression Omnibus datasets (GSE13507 and GSE32894) and the Xiangya cohort (RNA-sequencing 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 with TNF cluster 2. We then filtered out 196 differentially expressed genes 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. Conclusion: 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.
| S-EPMC8842074 | biostudies-literature
Project description:Glioblastomas display cellular hierarchies with self-renewing tumor-initiating cells (TIC), also known as cancer stem cells, at the apex. Although the TIC hypothesis remains controversial and the functional assays to define the TIC phenotype are evolving, we and others have shown that TICs may contribute to therapeutic resistance, tumor spread, and angiogenesis. The identification of TICs has been informed by the use of markers characterized in normal stem cells, but this approach has an inherent limitation to selectively identify TICs. To develop reagents that enrich TICs but not matched non-TICs or tissue-specific stem cells, we adopted Cell-Systematic Evolution of Ligands by Exponential Enrichment (Cell-SELEX) to identify glioblastoma TIC-specific nucleic acid probes-aptamers-that specifically bind TICs. In this study, using Cell-SELEX with positive selection for TICs and negative selection for non-TICs and human neural progenitor cells, we identified TIC aptamers that specifically bind to TICs with excellent dissociation constants (Kd). These aptamers select and internalize into glioblastoma cells that self-renew, proliferate, and initiate tumors. As aptamers can be modified to deliver payloads, aptamers may represent novel agents that could selectively target or facilitate imaging of TICs.
| S-EPMC3933790 | biostudies-literature
Project description:BackgroundThioesterase superfamily member 6 (THEM6) has been implicated in the development and progression of various cancers. However, prior research emphasized on its regulatory role merely, we aim to investigate the effect of THEM6 gene on the immunological role and its relationship with molecular subtype in bladder cancer (BLCA).MethodsThrough pan-cancer analysis, we explored the THEM6 expression pattern and immunological role using The Cancer Genome Atlas (TCGA) database. In addition, we performed a correlation of THEM6 and its immunological functions, including immunomodulators, immune checkpoints, cancer immunity cycles, T cell inflamed score, and tumor-infiltrating immune cells in the BLCA tumor microenvironment (TME) based on TCGA and BLCA microarray cohort from Xiangya Hospital. We also assessed the accuracy of THEM6 in predicting the molecular subtype and its response to different interventions in BLCA. Finally, we computed and validated a prediction model established by THEM6-related different expressed immune-related genes that might help in BLCA prognosis.ResultsTHEM6 led to immunosuppression in BLCA TME. Furthermore, there was a downregulation in the immunological functions. Besides, THEM6 could effectively distinguish BLCA molecular subtypes, and THEM6 low expression implied basal subtype that was more effective to several interventions, such as immune checkpoint blockade (ICB) therapies, neoadjuvant chemotherapy, and radiotherapy. While THEM6 high expression indicated luminal subtype, hyperprogression and better response to targeted therapies, such as blocking THEM6 and several immune-inhibited oncogenic pathways.ConclusionsTHEM6 may be with potential immune-modulating properties and may become a potential new immunotherapy target for BLCA. THEM6 could accurately predict the molecular subtype of BLCA, which was helpful for guiding the treatment. Simultaneously, the prediction model may exhibit an excellent predictive value in patients with BLCA.
| S-EPMC9334031 | biostudies-literature