Development of myeloid-derived suppressor cells (MDSC) targeted therapy for the treatment of cisplatin-resistant bladder cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 415-415
Author(s):  
Yuji Takeyama ◽  
Minoru Kato ◽  
Yasuomi Shimizu ◽  
Kosuke Hamada ◽  
Taro Iguchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Suppressor Cells ◽  
Bladder Cancer Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Expression Levels ◽  
Tumor Bearing ◽  
Gene Expression Levels

415 Background: The emergence of immune checkpoint inhibitors (ICI) has brought hope for cure and survival for those suffering from various cancers, including bladder cancer. However, the response rate of ICI monotherapy is modest, and recent reports indicate that myeloid-derived suppressor cells (MDSC) might play a role in the resistant mechanism of ICI. In this study, we assess the effect of chemokine signal on the proliferation of bladder cancer and investigate whether MDSC could be a new target for the treatment of cisplatin-resistant bladder cancer. Methods: We established a cisplatin resistant strain (MB49R) of mice bladder cancer cell line MB49, and examined the alteration of the expression levels of inflammatory chemokines by chemokine array. Next, we isolated MDSCs from spleen and tumor in tumor-bearing mice to examine gene expression levels of chemokine receptors (CXCR2 and CCR2) and immunosuppression genes (Arg-1 and iNOS). Furthermore, we assessed the efficacy of CDDP, α-PD-L1 and chemokine antagonists against the proliferation of tumors in MB49 and MB49R xenograft models. Results: Expression levels of CCL2 and CXCL1/2, which are involved in the migration of MDSC, were significantly increased in the culture supernatant of MB49R compared to those in MB49 cell lines. This result was confirmed by real-time RT-qPCR of tumor extract, and this increase was also observed in human bladder cancer cell lines (T24 and T24R). CXCR2 and CCR2 were highly expressed in PMN-MDSC and M-MDSC, respectively, which were isolated from spleen or tumors in tumor-bearing mice, and gene expression levels of Arg-1 and iNOS were dramatically increased in M-MDSCs from the tumor tissues compared to those from spleen. Also, analysis by flow cytometry revealed that PMN-MDSC dramatically decreased in MB49R compared to parental MB49 tumors, while the proportion of M-MDSC was not changed in MB49R, which indicates that M-MDSC could be a target for the treatment of CDDP resistant bladder cancer. Conclusions: The results in the present study might indicate that the combination treatment with ICI and MDSC-targeting therapy could be an option for the treatment of cisplatin-resistant bladder cancer.

Heterogeneity in Nectin-4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 463-463
Author(s):  
Carissa Chu ◽  
Martin Sjöström ◽  
Emily A Egusa ◽  
Ewan Gibb ◽  
Michelle L Badura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Urothelial Cancer ◽  
Molecular Subtypes ◽  
Cancer Cell Lines ◽  
Bladder Cancer Cell ◽  
Antibody Drug Conjugate ◽  
Metastatic Urothelial Cancer

463 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting Nectin-4 (encoded by the PVRL4/NECTIN4 gene ) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In the present study, we sought to 1) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and 2) determine if Nectin-4 expression mediates EV sensitivity or resistance. Methods: NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1912 total patients) were used to compare relative NECTIN4 expression across molecular subtypes. The outcome of the gene expression analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in multiple bladder cancer cell lines. NECTIN4 was stably over-expressed or knocked down in basal (TCCSUP and UMUC-3) and luminal (HT-1376, HT-1197 and UMUC-9) bladder cancer cell lines, respectively, and EV dose-response assays were performed, as measured by cell proliferation and clonogenic assays. Results: NECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes (p < 0.001). NECTIN4 expression is positively correlated with the luminal markers GATA3, FOXA1, and PPARG across cohorts (Spearman’s rank correlation r = 0.57, p < 0.0001 for GATA3, r = 0.37, p < 0.0001 for FOXA1, and r = 0.56, p < 0.0001 for PPARG). NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 led to EV resistance, and EV-resistant cell lines expressed decreased levels of Nectin-4. Conclusions: Results of this pre-clinical study suggest that sensitivity to EV is mediated by expression of NECTIN4, which is significantly enriched in luminal subtypes of bladder cancer. Downregulation of NECTIN4 leads to resistance to EV. These findings have implications for biomarker development, patient selection and the inclusion of molecular subtyping in ongoing and future EV clinical trials. Further investigation into Nectin-4 loss as a mechanism of resistance in patients treated on EV is warranted.

scholarly journals Evaluation of retinoblastoma (Rb) and protein-53 (p53) gene expression levels in breast cancer cell lines (MCF-7) induced with some selected cytotoxic plants

2013 ◽  
Vol 5 (7) ◽  
pp. 120-126 ◽  
Author(s):  
Titilola Aderonke Samuel ◽  
Ayorinde Babatunde James ◽  
Temitope Adesola Oshodi ◽  
Uchennaya Okereke Odii ◽  
Innocent Chidume ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
P53 Gene ◽  
Breast Cancer Cell Lines ◽  
Expression Levels ◽  
Gene Expression Levels ◽  
Mcf 7

scholarly journals Evaluation of CERS2 Gene as a Potential Biomarker for Bladder Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Ahmed Faris Aldoghachi ◽  
Aminuddin Baharudin ◽  
Umar Ahmad ◽  
Soon Choy Chan ◽  
Teng Aik Ong ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Predictive Biomarker ◽  
Cancer Cell Lines ◽  
Bladder Cancer Cell ◽  
Ceramide Synthase ◽  
Expression Levels ◽  
Potential Biomarker ◽  
Different Types

The ceramide synthase 2 (CERS2) gene has been linked to tumour recurrence and invasion in many different types of cancers including bladder cancer. In this study, the expression levels of CERS2 in bladder cancer cell lines were analysed using qRT-PCR and the protein expression in clinical bladder cancer histopathological specimens were examined via immunohistochemistry. The potential utility of CERS2 as a predictive biomarker of response to oncolytic virotherapy was assessed by correlating the CERS2 mRNA expression to IC50 values of cells treated with the Newcastle disease virus (NDV), AF2240 strain. This study demonstrates that CERS2 is differentially expressed in different types of bladder cancer cell lines and that the siRNA-mediated downregulation of the expression of CERS2 reduces the migratory potential of UMUC1 bladder cancer cells. However, there were no significant correlations between the expression levels of the CERS2 protein with bladder cancer grade/stage or between the IC50 values of cells treated with NDV and CERS2 expression. Although the utility of CERS2 expression may be limited, its potential as an antimigration cancer therapeutic should be further examined.

916 GENE EXPRESSION CHANGES AS RESISTANT MARKERS TO CISPLATIN IN A PANEL OF BLADDER CANCER CELL LINES

2013 ◽  
Vol 189 (4S) ◽  
Author(s):  
Sung Han KIM ◽  
Hyunjin JIN ◽  
Sang Chul Lee ◽  
Eun-Sik Lee ◽  
Sang Eun Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Bladder Cancer Cell

scholarly journals CellExpress: a comprehensive microarray-based cancer cell line and clinical sample gene expression analysis online system

Database ◽  
2018 ◽  
Vol 2018 ◽  
Author(s):  
Yi-Fang Lee ◽  
Chien-Yueh Lee ◽  
Liang-Chuan Lai ◽  
Mong-Hsun Tsai ◽  
Tzu-Pin Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Cancer Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Comprehensive Analysis ◽  
Next Generation Sequencing Data ◽  
Clinical Samples ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract With the advancement of high-throughput technologies, gene expression profiles in cell lines and clinical samples are widely available in the public domain for research. However, a challenge arises when trying to perform a systematic and comprehensive analysis across independent datasets. To address this issue, we developed a web-based system, CellExpress, for analyzing the gene expression levels in more than 4000 cancer cell lines and clinical samples obtained from public datasets and user-submitted data. First, a normalization algorithm can be utilized to reduce the systematic biases across independent datasets. Next, a similarity assessment of gene expression profiles can be achieved through a dynamic dot plot, along with a distance matrix obtained from principal component analysis. Subsequently, differentially expressed genes can be visualized using hierarchical clustering. Several statistical tests and analytical algorithms are implemented in the system for dissecting gene expression changes based on the groupings defined by users. Lastly, users are able to upload their own microarray and/or next-generation sequencing data to perform a comparison of their gene expression patterns, which can help classify user data, such as stem cells, into different tissue types. In conclusion, CellExpress is a user-friendly tool that provides a comprehensive analysis of gene expression levels in both cell lines and clinical samples. The website is freely available at http://cellexpress.cgm.ntu.edu.tw/. Source code is available at https://github.com/LeeYiFang/Carkinos under the MIT License. Database URL: http://cellexpress.cgm.ntu.edu.tw/

Metallothionein isoform gene expression in four human bladder cancer cell lines

1999 ◽  
pp. 607-612 ◽  
Author(s):  
Scott H. Garrett ◽  
Seema Somji ◽  
John H. Todd ◽  
Donald A. Sens ◽  
Donald L. Lamm ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Bladder Cancer Cell ◽  
Human Bladder Cancer ◽  
Human Bladder ◽  
Human Bladder Cancer Cell

scholarly journals Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer

2018 ◽  
Vol 19 (9) ◽  
pp. 2694 ◽  
Author(s):  
Manh-Hung Do ◽  
Phuong To ◽  
Young-Suk Cho ◽  
Se-Young Kwon ◽  
Eu Hwang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Efficacy ◽  
Cancer Gene Therapy ◽  
Bladder Cancer Cell ◽  
Cancer Gene ◽  
Expression Levels

CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

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