The prognostic value of cytokeratin and extracellular collagen expression in urinary bladder cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Marc Ingenwerth ◽  
Péter Nyirády ◽  
Boris Hadaschik ◽  
Tibor Szarvas ◽  
Henning Reis
Keyword(s):  
Bladder Cancer ◽  
Protein Expression ◽  
Urinary Bladder Cancer ◽  
High Expression ◽  
Low Grade ◽  
Mrna Levels ◽  
High Grade ◽  
Expression Levels ◽  
Gene And Protein Expression ◽  
Muscle Invasive

Background: Expression levels of collagens have been implicated in the progression of various cancers and interact with cytokeratins, but are not well studied in bladder cancer (BC). Therefore, we analyzed the gene and protein expression levels of collagen 1A1 (Col1a1/COL1A1), collagen 3A1 (col3a1/COL3A1), collagen 5A2 (col5a2/COL5A2), cytokeratin 14 (krt14/CK14), and cytokeratin 17 (krt17/CK17) in urothelial BC samples of different stages. Methods: In total, 102 fresh frozen and 190 formalin fixed and paraffin embedded (FFPE) samples were tested using immunohistochemistry and RT-qPCR. Expression levels were correlated to clinicopathological and follow-up data. Results: Col1a1, col3a1, col5a2 and krt14 mRNA levels were significantly overexpressed in high-grade and muscle-invasive BC (MIBC) compared to low-grade and non-muscle invasive BC (NMIBC) cases. Disease-specific survival (DSS) was shorter in patients with high expression levels of col1a1 (p = 0.004), col3a1 (p = 0.004), and col5a2 (p = 0.028). CK14 (p = 0.020), COL3A1 (p = 0.006) and Col5A2 (p = 0.006) protein expression levels were significantly higher and protein expression levels of CK17 (p = 0.05) significantly lower in MIBC compared to NMIBC. Furthermore, CK14 (p = 0.002) and COL5A2 (p = 0.006) protein expressions were significantly higher in high-grade compared to low-grade BC. DSS was shorter in patients with high expression levels of COL5A2 (p = 0.033) and CK14 (p = 0.042). Conclusion: Expression changes of collagens and cytokeratins are univariable prognostic markers in BC.

Utility of first order MRI-Texture analysis parameters in the prediction of histologic grade and muscle invasion in urinary bladder cancer: a preliminary study

2021 ◽  
pp. 20201114
Author(s):  
Abdul Razik ◽  
Chandan J Das ◽  
Raju Sharma ◽  
Sundeep Malla ◽  
Sanjay Sharma ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urinary Bladder ◽  
Texture Analysis ◽  
Urinary Bladder Cancer ◽  
Histologic Grade ◽  
Low Grade ◽  
High Grade ◽  
First Order ◽  
Muscle Invasive ◽  
Muscle Invasion

Objective: To explore the utility of first-order MRI-texture analysis (TA) parameters in predicting histologic grade and muscle invasion in urinary bladder cancer (UBC). Methods: After ethical clearance, 40 patients with UBC, who were imaged on a 3.0-Tesla scanner, were retrospectively included. Using the TexRADTM platform, two readers placed freehand ROI on the sections demonstrating the largest dimension of the tumor, evaluating only one tumor per patient. Interobserver reproducibility was assessed using the intraclass correlation coefficient (ICC). Mann–Whitney U test and ROC curve analysis were used to identify statistical significance and select parameters with high class separation capacity (AUC >0.8), respectively. Pearson’s test was used to identify redundancy in the results. Results: All texture parameters showed excellent ICC. The best parameters in differentiating high and low-grade tumors were mean/ mean of positive pixels (MPP) at SSF 0 (AUC: 0.897) and kurtosis at SSF 5 (AUC: 0.828) on the ADC images. In differentiating muscle invasive from non-muscle invasive tumors, mean/ MPP at SSF 0 on the ADC images showed AUC >0.8; however, this finding resulted from the confounding effect of high-grade histology on the ADC values of muscle invasive tumors. Conclusion: MRI-TA generated few parameters which were reproducible and useful in predicting histologic grade. No independent parameters predicted muscle invasion. Advances in knowledge: There is lacuna in the literature concerning the role of MRI-TA in the prediction of histologic grade and muscle invasion in UBC. Our study generated a few first-order parameters which were useful in predicting high-grade histology.

Erythroid-Expression of HMGA2 Increases Fetal Hemoglobin in Human Adult Erythroblasts

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2161-2161
Author(s):  
Jaira F. de Vasconcellos ◽  
Y. Terry Lee ◽  
Colleen Byrnes ◽  
Laxminath Tumburu ◽  
Antoinette Rabel ◽  
...  
Keyword(s):  
Protein Expression ◽  
Fetal Hemoglobin ◽  
Cell Counting ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Globin Mrna ◽  
Expression Levels ◽  
Gamma Globin ◽  
Empty Vector ◽  
Gene And Protein Expression

Abstract HMGA2 is a member of the high-mobility group A family and plays a role in the regulation of gene transcription and chromatin structure. HMGA2 is a validated target of the let-7 family of miRNAs. Let-7 miRNAs are highly regulated in erythroid cells during the fetal-to-adult developmental transition (1). Recent studies demonstrated that the LIN28 -let-7 axis mediated up-regulation of fetal hemoglobin (HbF) expression to >30% of the total globin levels in cultured erythroblasts from adult humans (2) and the amelioration of hypoxia-related sickling of cultured mature erythrocytes from pediatric patients with sickle cell disease (3). Interestingly, increased expression of endogenous HbF in a patient receiving gene therapy was also associated with truncated HMGA2 protein expression after lentiviral integration and disruption of let-7 targeting at the HMGA2 gene locus (4). Therefore, we hypothesized that HMGA2 may be involved in fetal hemoglobin regulation as a downstream target of the let-7 miRNAs. To study the effects of HMGA2 upon erythropoiesis and globin expression, lentiviral constructs were designed for let-7 resistant expression of HMGA2 driven by the erythroid-specific gene promoter region of the human SPTA1 gene (HMGA2 -SPTA1-OE), with a matched empty vector control. Transductions were performed in CD34+ cells from four adult healthy volunteers cultivated ex vivo in erythropoietin-supplemented serum-free media for 21 days. Overexpression of HMGA2 was confirmedby Q-RT-PCR (control: below detection limits; HMGA2 -SPTA1-OE: 2.51E+04 ± 3.44E+04 copies/ng) and Western blot analyses at culture day 14. Cell counting revealed no significant changes between HMGA2 -SPTA1-OE and control (empty vector) transductions at culture day 14. Terminal maturation with loss of CD71 from the erythroblast cell surface and enucleation assessed by thiazole orange staining were analyzed in the control and HMGA2 -SPTA1 -OE samples at the end of the culture period. Globin genes expression levels were evaluated for HMGA2 -SPTA1-OE by Q-RT-PCR. HMGA2 -SPTA1-OE caused a significant increase in gamma-globin mRNA expression levels compared to controls (control: 5.02E+05 ± 8.62E+04 copies/ng; HMGA2 -SPTA1-OE: 1.45E+06 ± 7.31E+05 copies/ng; p=0.037). Consistent with the increase in gamma-globin mRNA levels, HPLC analyses at culture day 21 demonstrated modest but significant increases in HbF levels in HMGA2 -SPTA1-OE compared to controls (HbF control: 5.41 ± 2.15%; HMGA2 -SPTA1-OE: 16.53 ± 4.43%; p=0.006). Possible effect(s) and downstream mechanism(s) triggered by HMGA2 -SPTA1-OE were investigated. Q-RT-PCR analyses demonstrated no significant changes in the let-7 family of miRNAs in HMGA2 -SPTA1-OE compared to controls. Expression patterns of several transcription factors such as BCL11A, KLF1, SOX6 and GATA1 were investigated by Q-RT-PCR and no significant changes were detected in HMGA2 -SPTA1-OE compared to controls. While BCL11A mRNA levels were decreased by HMGA2 -SPTA1 -OE, the differences did not reach statistical significance (control: 4.26E+02 ± 8.18E+01 copies/ng; HMGA2 -SPTA1 -OE: 2.84E+02 ± 1.48E+02 copies/ng; p=0.104). However, nuclear BCL11A protein levels assessed by Western analysis were suppressed in HMGA2 -SPTA1 -OE. In summary, these results demonstrate that HMGA2, a validated target of let-7 miRNAs, causes moderately increased gamma-globin gene and protein expression in human erythroblasts, and reduces levels of BCL11A protein. These data thus support the notion that suppression of let-7 miRNAs increases fetal hemoglobin, in part, by the targeting of erythroblast HMGA2 mRNA. (1) Noh SJ et al. J Transl Med. 7:98 (2009). (2) Lee YT et al. Blood. 122:1034-41 (2013). (3) Vasconcellos JF et al. PLoS One. 9:e106924 (2014). (4) Cavazzana-Calvo M et al. Nature. 467:318-22 (2010). Disclosures No relevant conflicts of interest to declare.

scholarly journals A Single-Institutional Study of Human Immunodeficiency Virus-Related Bladder Cancer

2021 ◽  
Author(s):  
Mengmeng Zhang ◽  
Yanyan Zhang ◽  
Zhiqiang Zhu ◽  
Yu Zhang
Keyword(s):  
Bladder Cancer ◽  
Cancer Patients ◽  
Clinical Characteristics ◽  
Transitional Cell ◽  
Invasive Bladder Cancer ◽  
Low Grade ◽  
High Grade ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Pathology ◽  
Muscle Invasive

Abstract Purpose: We wished to investigate the clinical characteristics, treatments for tumor, pathology and outcomes of bladder cancer patients with HIV-infected.Patients and methods: We identified 10 cases of bladder cancer with HIV-infected from 2015 to 2020.We retrospectively investigated the clinical characteristics of the cases including demographic information, clinical presentation, TNM stage and so on. We investigated treatments for tumor, pathology, outcomes and HIV-relevant parameters during patients’ hospitalization course as well. Results: In our study, it was astonished to find that bladder cancer patients with HIV-infected were males at the median age of 51 years old, and no females were diagnosed on the contrary. Nine (90%)patients presented with painless gross hematuria, while one patient with incidental findings on ultrasonic examination. Six(60%) patients co-infected with another kind of infectious disease, four with syphilis, and two with HBV respectively. The median CD4+ T-lymphocyte cell count was 493/ul withthin 2 weeks prior to the diagnosis bladder cancer. Cystoscope examination manifested that the lesions were located in the trigonum of the bladder in four(40%)patients. All patients underwent surgeries successfully, six underwent transurethral resection of bladder tumor(TURBT),two of whom relapsed once, and one underwent TURBT twice due to recurrence and then RC and urethrectomy because of urethral invasion. All non muscle-invasive bladder cancer(NMIBC)patients received intravesical chemotherapy with pirarubicin 30mg for at least half year conventionally, and only one patient occurred mild adverse reaction of irritative symptoms of bladder. Pathologic analysis documented that all patients(100%) had transitional cell carcinoma(TCC). Tumor grade classification showed that three cases were identified with low grade TCC, and six cases with high grade or invasive TCC, two of whom occurred recurrence for once or twice respectively. One patient was identified with low grade TCC of primary tumor and high grade TCC of recurrent focal(Figure 2).Five cases(50%) were ascertained as (NMIBC) with pT1N0M0, while the rest five patients(50%) were muscle-invasive bladder cancer(MIBC) with at least pT2N0M0. During the median follow-up of 56 months (range from 5 months to 68 months) six cases(five were MIBC patients )died due to distant metastases. No patients acceptted adjuvent immunotherapy mainly due to the role of PD-1+ T cells in HIV transcription in treated aviremic individuals, concerns of unknown adverse effects and economic factors.Conclusions: It seemed like that bladder caner patients had higher tumor stage and more aggressive pathology. we did not find any evidence on the relationship between immunodeficiency and cancer progression because of relatively stable HIV status of this crew in our study. MIBC patients with HIV-infected really have worse outcomes, and more attention is warranted to pay to this special population in this situation when they present with hematuria extraordinarily.

Comprehensive targeted gene profiling to determine the genomic signature likely to drive progression of high-grade nonmuscle invasive bladder cancer to muscle invasive bladder cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 568-568
Author(s):  
Abedalrhman Alkhateeb ◽  
Govindaraja Atikukke ◽  
Lisa Porter ◽  
Bre-Anne Fifield ◽  
Dora Cavallo-Medved ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Gene Profiling ◽  
Invasive Bladder Cancer ◽  
Low Grade ◽  
Genomic Profiling ◽  
High Grade ◽  
Single Nucleotide Variants ◽  
Muscle Invasive Bladder Cancer ◽  
Non Invasive ◽  
Muscle Invasive

568 Background: Bladder cancer is the fifth most common cancer and eighth leading cause of cancer related-death in North America. It can present as non-muscle invasive bladder cancer (NMIBC) and/or muscle invasive bladder (MIBC). Although genomic profiling studies have established that low-grade NMIBC and MIBC are genetically distinct, high-grade NMIBC can recur and progress to MIBC [ Knowles, M.A. and C.D. Hurst, 2015]. Low grade, non-invasive bladder cancers are characterized by activating mutations in fibroblast growth factor receptor 3 (FGFR3), HRAS or other pathways of receptor kinase activation. High-grade disease, which is often becomes invasive, is characterized by inactivation of TP53 and Rb pathways [Kim, J., et al.]. Finding a subtype of invasive carcinoma with FGFR3 mutation may suggest an alternate pathway by which low grade, non-invasive pathology could transform into invasive disease [Knowles, M.A. and C.D. Hurst, 2015]. Methods: In this study, using a total of 30 bladder cancer (NMIBC and MIBC) patient samples from Windsor Regional Hospital Cancer Program, we performed comprehensive targeted gene sequencing to identify single nucleotide variants, small insertions / deletions, copy number variants and splice variants in over 500 common tumor genes panel. Results: Preliminary data from our study correlates with previously published mutation landscape for NMIBC and MIBC, and includes mutations in EGFR, FGFR3, FGFR4, PIK3CA, CDK6, ALK, JAK, as well as RET. While mutations in AKT1, BRCA1, CCND1, ERBB2, FGFR1, FGFR2, HRAS, and MET appear to be prevalent in NMIBC, mutations in IDH1 and MAP2K2 appear to be more common in MIBC. Three of the samples used in the study are from patients who progressed from high-grade NMIBC to MIBC. Conclusions: Therefore, have the genomic profiling performed at these two stages, which provides a unique ability to identify the potential “genomic triggers” for the transition.

scholarly journals Stem-Like Signature Predicting Disease Progression in Early Stage Bladder Cancer. The Role of E2F3 and SOX4

Biomedicines ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 85 ◽  
Author(s):  
Joaquim Bellmunt
Keyword(s):  
Stem Cells ◽  
Bladder Cancer ◽  
Cancer Stem Cells ◽  
Tumor Progression ◽  
Cell Types ◽  
Invasive Bladder Cancer ◽  
Low Grade ◽  
High Grade ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

The rapid development of the cancer stem cells (CSC) field, together with powerful genome-wide screening techniques, have provided the basis for the development of future alternative and reliable therapies aimed at targeting tumor-initiating cell populations. Urothelial bladder cancer stem cells (BCSCs) that were identified for the first time in 2009 are heterogenous and originate from multiple cell types; including urothelial stem cells and differentiated cell types—basal, intermediate stratum and umbrella cells Some studies hypothesize that BCSCs do not necessarily arise from normal stem cells but might derive from differentiated progenies following mutational insults and acquisition of tumorigenic properties. Conversely, there is data that normal bladder tissues can generate CSCs through mutations. Prognostic risk stratification by identification of predictive markers is of major importance in the management of urothelial cell carcinoma (UCC) patients. Several stem cell markers have been linked to recurrence or progression. The CD44v8-10 to standard CD44-ratio (total ratio of all CD44 alternative splicing isoforms) in urothelial cancer has been shown to be closely associated with tumor progression and aggressiveness. ALDH1, has also been reported to be associated with BCSCs and a worse prognosis in a large number of studies. UCC include low-grade and high-grade non-muscle invasive bladder cancer (NMIBC) and high-grade muscle invasive bladder cancer (MIBC). Important genetic defects characterize the distinct pathways in each one of the stages and probably grades. As an example, amplification of chromosome 6p22 is one of the most frequent changes seen in MIBC and might act as an early event in tumor progression. Interestingly, among NMIBC there is a much higher rate of amplification in high-grade NMIBC compared to low grade NMIBC. CDKAL1, E2F3 and SOX4 are highly expressed in patients with the chromosomal 6p22 amplification aside from other six well known genes (ID4, MBOAT1, LINC00340, PRL, and HDGFL1). Based on that, SOX4, E2F3 or 6q22.3 amplifications might represent potential targets in this tumor type. Focusing more in SOX4, it seems to exert its critical regulatory functions upstream of the Snail, Zeb, and Twist family of transcriptional inducers of EMT (epithelial–mesenchymal transition), but without directly affecting their expression as seen in several cell lines of the Cancer Cell Line Encyclopedia (CCLE) project. SOX4 gene expression correlates with advanced cancer stages and poor survival rate in bladder cancer, supporting a potential role as a regulator of the bladder CSC properties. SOX4 might serve as a biomarker of the aggressive phenotype, also underlying progression from NMIBC to MIBC. The amplicon in chromosome 6 contains SOX4 and E2F3 and is frequently found amplified in bladder cancer. These genes/amplicons might be a potential target for therapy. As an existing hypothesis is that chromatin deregulation through enhancers or super-enhancers might be the underlying mechanism responsible of this deregulation, a potential way to target these transcription factors could be through epigenetic modifiers.

scholarly journals UBC®Rapid Test for detection of carcinoma in situ for bladder cancer

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770162 ◽  
Author(s):  
Thorsten H Ecke ◽  
Sarah Weiß ◽  
Carsten Stephan ◽  
Steffen Hallmann ◽  
Dimitri Barski ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urinary Bladder ◽  
Carcinoma In Situ ◽  
Rapid Test ◽  
Control Group ◽  
Low Grade ◽  
High Grade ◽  
Healthy Controls ◽  
Muscle Invasive

UBC® Rapid Test is a test that detects fragments of cytokeratins 8 and 18 in urine. We present results of a multicentre study measuring UBC® Rapid Test in bladder cancer patients and healthy controls with focus on carcinoma in situ (CIS) and high-grade bladder cancer. From our study with N = 452 patients, we made a stratified sub-analysis for carcinoma in situ of the urinary bladder. Clinical urine samples were used from 87 patients with tumours of the urinary bladder (23 carcinoma in situ, 23 non-muscle-invasive low-grade tumours, 21 non-muscle-invasive high-grade tumours and 20 muscle-invasive high-grade tumours) and from 22 healthy controls. The cut-off value was defined at 10.0 µg/L. Urine samples were analysed by the UBC® Rapid Test point-of-care system (concile Omega 100 POC reader). Pathological levels of UBC Rapid Test in urine are higher in patients with bladder cancer in comparison to the control group (p < 0.001). Sensitivity was calculated at 86.9% for carcinoma in situ, 30.4% for non-muscle-invasive low-grade bladder cancer, 71.4% for nonmuscle-invasive high grade bladder cancer and 60% for muscle-invasive high-grade bladder cancer, and specificity was 90.9%. The area under the curve of the quantitative UBC® Rapid Test using the optimal threshold obtained by receiveroperated curve analysis was 0.75. Pathological values of UBC® Rapid Test in urine are higher in patients with high-grade bladder cancer in comparison to low-grade tumours and the healthy control group. UBC® Rapid Test has potential to be more sensitive and specific urinary protein biomarker for accurate detection of high-grade patients and could be added especially in the diagnostics for carcinoma in situ and non-muscle-invasive high-grade tumours of urinary bladder cancer.

scholarly journals Molecular Pathways in Low and High-grade Non-muscle Invasive Bladder Cancer as Revealed by Several OMICs Data Analyses

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Somaye Zareian ◽  
Saghar Pahlavanneshan
Keyword(s):  
Bladder Cancer ◽  
Data Analysis ◽  
Microarray Data ◽  
Microarray Data Analysis ◽  
Low Grade ◽  
Molecular Pathways ◽  
High Grade ◽  
Hub Genes ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

Background: Bladder cancer is one of the most prevalent cancers, accounting for 2.1% of cancer mortalities worldwide. Bladder cancer is categorized into non-muscle invasive and muscle-invasive bladder cancers. Non-muscle invasive bladder cancer (NMIBC) is the most common and widely heterogeneous type with different outcomes. Objectives: This study was designed to categorize NMIBC tumor grade based on microarray data analysis. Methods: We performed microarray data analysis using GSE7476, GSE13507, and GSE37815 in patients diagnosed with NMIBC. Differentially expressed genes (DEGs) were identified based on low-grade and high-grade NMIBC. Protein-protein interaction (PPI) network analysis was carried out, and hub genes and underlying molecular pathways were identified. Results: We observed low-grade Hub genes, including GAS6, TGFB3, TPM1, COL5A1, COL1A2, SERPING1, ACTA2, TPM2, SDC1, and A2M involved in a variety of gene ontology (GO) biological processes, while high-grade genes were involved in cell cycle and cell division. The most relevant pathways suggested for low-grade NMIBC were extracellular matrix organization, platelet degranulation, and muscle contraction. Conclusions: The identification of gene hubs and underlying pathways in several low and high-grade NMIBC samples may offer better treatment management and prognostication based on molecular profiling.

Sign in / Sign up

Export Citation Format

Share Document