Cancer stem cell-specific expression profiles reveal emerging bladder cancer biomarkers and identify circRNA_103809 as an important regulator in bladder cancer.
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ABSTRACT:
SUBMITTER: Tao T
PROVIDER: S-EPMC7066924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bladder cancer is a very common malignancy. Although new treatment strategies have been developed, the identification of new therapeutic targets and reliable diagnostic/prognostic biomarkers for bladder cancer remains a priority. Generally, they are found among differentially expressed genes between patients and healthy subjects or among patients with different tumor stages. However, the classical approach includes processing these data taking into consideration only the expression of each single gene regardless of the expression of other genes. These complex gene interaction networks can be revealed by a recently developed systems biology approach called Weighted Gene Co-expression Network Analysis (WGCNA). It takes into account the expression of all genes assessed in an experiment in order to reveal the clusters of co-expressed genes (modules) that, very probably, are also co-regulated. If some genes are co-expressed in controls but not in pathological samples, it can be hypothesized that a regulatory mechanism was altered and that it could be the cause or the effect of the disease. Therefore, genes within these modules could play a role in cancer and thus be considered as potential therapeutic targets or diagnostic/prognostic biomarkers. Here, we have reviewed all the studies where WGCNA has been applied to gene expression data from bladder cancer patients. We have shown the importance of this new approach in identifying candidate biomarkers and therapeutic targets. They include both genes and miRNAs and some of them have already been identified in the literature to have a role in bladder cancer initiation, progression, metastasis, and patient survival.
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Project description:DNA methylation profiles can be used to define molecular cancer subtypes that may better inform disease etiology and clinical decision-making. This investigation aimed to create DNA methylation profiles of bladder cancer based on CpG methylation from almost 800 cancer-related genes and to then examine the relationship of those profiles with exposures related to risk and clinical characteristics. DNA, derived from formalin-fixed paraffin-embedded tumor samples obtained from incident cases involved in a population-based case-control study of bladder cancer in New Hampshire, was used for methylation profiling on the Illumina GoldenGate Methylation Bead Array. Unsupervised clustering of those loci with the greatest change in methylation between tumor and non-diseased tissue was performed to defined molecular subgroups of disease, and univariate tests of association followed by multinomial logistic regression was used to examine the association between these classes, bladder cancer risk factors and clinical phenotypes. Membership in the two most methylated classes was significantly associated with invasive disease (P < 0.001 for both class 3 and 4). Male gender (P = 0.04) and age >70 years (P = 0.05) was associated with membership in one of the most methylated classes. Finally, average water arsenic levels in the highest percentile predicted membership in an intermediately methylated class of tumors (P = 0.02 for both classes). Exposures and demographic associated with increased risk of bladder cancer specifically associate with particular subgroups of tumors defined by DNA methylation profiling and these subgroups may define more aggressive disease.
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Project description:Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. Despite aggressive therapy with surgery, radiotherapy, and chemotherapy, nearly all patients succumb to disease within 2 years. Several studies have supported the presence of stem-like cells in brain tumor cultures that are CD133-positive, are capable of self-renewal, and give rise to all cell types found within the tumor, potentially perpetuating growth. CD133 is a widely accepted marker for glioma-derived cancer stem cells; however, its reliability has been questioned, creating a need for other identifiers of this biologically important subpopulation. We used a panel of 20 lectins to identify differences in glycan expression found in the glycocalyx of undifferentiated glioma-derived stem cells and differentiated cells that arise from them. Fluorescently labeled lectins that specifically recognize ?-N-acetylgalactosamine (GalNAc) and ?-N-acetylglucosamine (GlcNAc) differentially bound to the cell surface based on the state of cellular differentiation. GalNAc and GlcNAc were highly expressed on the surface of undifferentiated cells and showed markedly reduced expression over a 12-day duration of differentiation. Additionally, the GalNAc-recognizing lectin Dolichos biflorus agglutinin was capable of specifically selecting and sorting glioma-derived stem cell populations from an unsorted tumor stock and this subpopulation had proliferative properties similar to CD133(+) cells in vitro and also had tumor-forming capability in vivo. Our preliminary results on a single cerebellar GBM suggest that GalNAc and GlcNAc are novel biomarkers for identifying glioma-derived stem cells and can be used to isolate cancer stem cells from unsorted cell populations, thereby creating new cell lines for research or clinical testing.
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Project description:Purpose of review: Inhibition of immune escape mechanisms, such as the programed death-ligand 1 pathway, has demonstrated rapid, durable responses in multiple tumor types, including advanced urothelial carcinoma. This review discusses emerging immunotherapies for urothelial carcinoma in various stages of clinical development.Recent findings: Urothelial carcinoma has a high mutational burden, which may increase the number of tumor antigens and potentially enhance the ability of the immune system to recognize tumor cells as foreign. However, urothelial carcinoma can evade the immune system by downregulating tumor-antigen presentation, upregulating various immune checkpoints, and inactivating cytotoxic T cells. Immunotherapies for urothelial carcinoma target each of these steps to restore immune-mediated cytotoxicity. Many of these agents are in clinical trials for urothelial carcinoma.Summary: Immunotherapies are active in urothelial carcinoma, but only in a fraction of patients, implying the presence of persistent immune escape. Identifying the mechanisms of immune escape and developing rational combinatorial regimens may make the benefit of immunotherapy accessible to a broader population.
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Project description:Bladder cancer ranks as the 10th most common cancer type globally, and muscle-invasive disease accounts for approximately 25% of newly diagnosed bladder cancers. Despite definitive treatment, 50% of patients with muscle-invasive bladder cancer (MIBC) develop metastasis within 2 years, leading to death. Perioperative systemic therapy is generally recommended to control local relapse or distant metastasis after surgical resection for patients with MIBC. Cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy is the current standard treatment to improve oncologic control and survival outcomes. Adjuvant chemotherapy is recommended for patients with pathological T3-4 or positive lymph nodes after radical cystectomy if no neoadjuvant chemotherapy was given. Nonetheless, perioperative systemic therapy is not applied widely because of its toxicity, and less than 25% of patients receive cisplatin-based neoadjuvant chemotherapy. Therefore, the development of predictive biomarkers for neoadjuvant chemotherapy efficacy and alternative effective regimens for cisplatin-ineligible patients are important. Furthermore, recently, novel anticancer agents such as immune checkpoint inhibitors and antibody-drug conjugates have proven survival benefits in the metastatic setting, thereby expanding their therapeutic applications to the perioperative setting for non-metastatic MIBC. Herein, we discuss the current status and future perspectives of perioperative systemic strategies for MIBC.
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Project description:Bladder cancer (BC) is a complex and highly heterogeneous stem cell disease associated with high morbidity and mortality rates if it is not treated properly. Early diagnosis with personalized therapy and regular follow-up are the keys to a successful outcome. Cancer stem cells (CSCs) are the leading power behind tumor growth, with the ability of self-renewal, metastasis, and resistance to conventional chemotherapy. The fast-developing CSC field with robust genome-wide screening methods has found a platform for establishing more reliable therapies to target tumor-initiating cell populations. However, the high heterogeneity of the CSCs in BC disease remains a large issue. Therefore, in the present review, we discuss the various types of bladder CSC heterogeneity, important regulatory pathways, roles in tumor progression and tumorigenesis, and the experimental culture models. Finally, we describe the current stem cell-based therapies for BC disease.
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Project description:Neoadjuvant chemoradiotherapy (nCRT) following surgery significantly improves the survival rate of patients with rectal cancer. However, nCRT is associated with significant adverse symptoms and high medical costs. Therefore, it is important to investigate potential biomarkers for the prediction of the response to nCRT in patients with rectal cancer. The present study identified candidate biomarkers for predicting a complete response (CR) to nCRT in patients with rectal cancer and investigated the associated mechanisms. Microarray data (accession no. GSE29298) was downloaded from the Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs/miR) were screened between the pathological CR (pCR) group and no pCR (incomplete response) group. miRNA target genes were predicted using the miRWalk 2.0 online tool and subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Furthermore, a miRNA co‑regulatory network was constructed and disease‑associated genes were predicted. The results demonstrated that a total of 36 upregulated and 5 downregulated miRNAs were identified between the two groups. Among these differentially expressed miRNAs, miR‑548c‑5p, miR‑548d‑5p and miR‑663a were significantly associated with a CR to nCRT. The co‑regulatory network and pathway analysis indicated that miR‑548c‑5p and miR‑548d‑5p may function together through stem cell pluripotency and ubiquitin‑mediated proteolysis signaling pathways. Furthermore, the prediction of disease‑associated genes demonstrated that miR‑548c‑5p/miR‑548d‑5p and miR‑663a may regulate genes associated with rectal cancer, including mutated in colorectal cancers (MCC) and adenomatous polyposis coli (APC), and colorectal neoplasms, including interleukin‑6 signal transducer (IL6ST), cell cycle checkpoint kinase 2 (CHEK2), marker of proliferation Ki‑67 (MKI67), cadherin 7 (CDH7), calreticulin (CALR) and transforming growth factor β1 (TGFB1). Therefore, miR‑548c‑5p, miR‑548d‑5p and miR‑663a are promising candidate biomarkers for predicting a CR to nCRT. miR‑548c‑5p/miR‑548d‑5p may be associated with a CR by regulating IL6ST, CHEK2, MKI67 and MCC. In addition, it may function through the pluripotency of stem cells and ubiquitin‑mediated proteolysis signaling pathways. miR‑663a may be associated with a CR to nCRT by targeting CDH7, CALR, APC and TGFβ1. Thus, the miRNA biomarkers investigated in the present study may represent novel therapeutic targets for the prediction and eventual improvement of the response to nCRT in patients with rectal cancer.
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Project description:Bladder cancer transformation and immortalization require the inactivation of key regulatory genes, including TP53. Genotyping of a large cohort of bladder cancer patients (n = 256) using the TP53 GeneChip showed mutations in 103 cases (40.2%), the majority of them mapping to the DNA-binding core domain. TP53 mutation status was significantly associated with tumor stage (P = 0.0001) and overall survival for patients with advanced disease (P = 0.01). Transcript profiling using oligonucleotide arrays was performed on a subset of these cases (n = 46). Supervised analyses identified genes differentially expressed between invasive bladder tumors with wild-type (n = 24) and mutated TP53 (n = 22). Pathway analyses of top-ranked genes supported the central role of TP53 in the functional network of such gene patterns. A proteomic strategy using reverse phase arrays with protein extracts of bladder cancer cell lines validated the association of identified differentially expressed genes, such as gelsolin, to TP53 status. Immunohistochemistry on tissue microarrays (n = 294) revealed that gelsolin was associated with tumor stage and overall survival, correlating positively with TP53 status in a subset of these patients. This study further reveals that TP53 mutations are frequent events in bladder cancer progression and identified gelsolin related to TP53 status, tumor staging, and clinical outcome by independent high-throughput strategies.
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Project description:ObjectiveCirculating tumor DNA (ctDNA) offers a minimally-invasive alternative to study genomic changes in recurrent malignancies. With a high recurrence rate, the overall survival in high-grade serous ovarian carcinoma (HGSC) has remained low. Our objectives were to determine whether ctDNA from plasma adequately represents HGSC, and to find mutational changes at relapse suggesting therapy options that could alter patient outcome.MethodsWe collected 152 longitudinal plasma and 92 fresh tissue samples from 29 HGSC patients, sequencing and detecting mutations with a gene panel of more than 700 cancer-related genes. Tumor content was measured using TP53 VAF. We analyzed the concordance between the mutations in tissue and plasma samples and calculated correlations to patient outcomes. We also searched for novel mutations appearing at relapse.ResultsThe concordance rate between mutations in plasma compared to tumor tissue was 83 % at diagnosis and 90 % at relapse. CtDNA was released similarly from the tubo-ovarian tumors, intra-abdominal metastases and ascites. CtDNA release was high when CA-125 level was elevated. The TP53 VAF in ctDNA from plasma samples before the third cycle of primary chemotherapy showed a negative correlation to patient outcome. At relapse, 19 novel, pathogenic DNA mutations appeared, suggesting possible actionable alterations and biological mechanisms related to chemoresistance.ConclusionRelapse ctDNA samples reflect tissue samples well and longitudinal sampling provides a timely source for mutational profiling. The emerging genetic mutations at recurrence propose that ctDNA accurately represents the widespread disease and provides possibilities for personalized therapy options.
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Project description:Bladder cancer is a molecularly heterogeneous disease characterized by multiple unmet needs in the realm of diagnosis, clinical staging, monitoring and therapy. There is an urgent need to develop precision medicine for advanced urothelial carcinoma. Given the difficulty of serial analyses of metastatic tumor tissue to identify resistance and new therapeutic targets, development of non-invasive monitoring using circulating molecular biomarkers is critically important. Although the development of circulating biomarkers for the management of bladder cancer is in its infancy and may currently suffer from lower sensitivity of detection, they have inherent advantages owing to non-invasiveness. Additionally, circulating molecular alterations may capture tumor heterogeneity without the sampling bias of tissue biopsy. This review describes the accumulating data to support further development of circulating biomarkers including circulating tumor cells, cell-free circulating tumor (ct)-DNA, RNA, micro-RNA and proteomics to improve the management of bladder cancer.
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