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      Co-Expression of Stem Cell and Epithelial Mesenchymal Transition Markers in Circulating Tumor Cells of Bladder Cancer Patients

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          Abstract

          Objective

          Cancer cells with stemness and epithelial-to-mesenchymal transition (EMT) features display enhanced malignant and metastatic potential. This study aimed to introduce a new methodology developed in order to investigate the co-expression of a stemness (OCT4) and EMT markers on single circulating tumor cells (CTCs) of patients with localized urinary bladder cancer and their potential prognostic prediction value.

          Methods and Materials

          Between April 2015 and July 2015, blood samples of 51 consecutive patients diagnosed with high risk bladder cancer (cT 1-3N 0M 0) were prospectively investigated for CTCs. Peripheral blood (5 mL) was drawn before primary transurethral resection. Detection of CTCs was performed using the CanPatrol TM system. Nucleic acid probes were used to identify CTCs, and expression levels of epithelial and mesenchymal genes in CTCs were examined by situ hybridization assay.

          Results

          All patients received radical cystectomy with pelvic lymph nodes dissection. CTCs were detected in 44 of 51 (86.3%) patients, respectively. The overall mean number of CTCs was 6.1 (range: 0~29; median: 4). A total of 311 CTCs were detected in PB. High OCT4 expression (OCT4 high) was detected more frequently in Epi Mes + cells (p=0.001). Patients with pathological confirmed muscle-invasive bladder cancer (MIBC) had higher Epi Mes + CTCs positive rates (p=0.001) and OCT4 high CTCs positive rates (p=0.019) than pathological confirmed non muscle-invasive bladder cancer (NMIBC). Regarding co-expression of these markers, Epi Mes +/OCT4 high CTCs were more frequently evident in the MIBC setting (30.4% vs 3.6% of patients, p = 0.016).

          Conclusion

          A differential expression pattern for these markers was observed both in NMIBC and MIBC disease. A subgroup of CTCs showed a CTCs expressing high OCT4, along with Mes were more frequently detected in patients with MIBC, suggesting that these cells may prevail during tumor muscle invasion and disease progression.

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          Most cited references 31

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          Cancer statistics, 2016.

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population.
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            Epithelial-mesenchymal transitions: twist in development and metastasis.

            Epithelial-mesenchymal transitions (EMT) are vital for morphogenesis during embryonic development and are also implicated in the conversion of early stage tumors into invasive malignancies. Several key inducers of EMT are transcription factors that repress E-cadherin expression. A recent report in Cell (Yang et al., 2004) adds Twist to this list and links EMT to the ability of breast cancer cells to enter the circulation and seed metastases.
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              Circulating tumor cells (CTC) detection: clinical impact and future directions.

              Recent molecular and clinical studies have shown that invasion may occur very early in tumor development, thus emphasizing the potential importance of specific and sensitive detection of circulating tumor cells (CTC) and circulating tumor microemboli (CTM). The technical challenge in this field consists of finding "rare" tumor cells (just a few CTCs mixed with the approximately 10 million leukocytes and 5 billion erythrocytes in 1ml of blood) and being able to distinguish them from epithelial non-tumor cells and leukocytes. Many recent studies have discussed the clinical impact of detecting CTC/CTM. Although conflicting results have been obtained, these studies suggest the vast potential of CTC/CTM detection in cancer prognosis and follow up. However, the variable technical approaches which were used, as well as the number of millilitres of blood analyzed, the quality of sensitivity and specificity tests, the number of patients versus controls and the data interpretation make it very difficult to draw firm conclusions. A particularly important recent finding is that invasive tumor cells tend to loose their epithelial antigens by the epithelial to mesenchymal transition (EMT) process. Furthermore, it is known that non-tumor epithelial cells can also be present in blood. Thus, it appears that a reliable diagnostic identification of CTC and CTM cannot be based on the expression of epithelial-specific transcripts or antigens. Cytopathological examination of CTC/CTM, sensitively enriched from blood, represents a potentially useful alternative and can now be employed in routine analyses as a specific diagnostic assay, and be tested in large, blind, multicenter clinical trials. This basic approach can be complemented by immunological and molecular studies for further characterization of CTC/CTM and of their malignant potential. This review is aimed at helping oncologists critically evaluate past and future research work in this field. The interest in development and assessment of this noninvasive marker should lead to more effective and better tailored anticancer treatments for individual patients, thus resulting in their improved life expectancy.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                ott
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                22 October 2020
                2020
                : 13
                : 10739-10748
                Affiliations
                [1 ]Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, People’s Republic of China
                [2 ]Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, People’s Republic of China
                Author notes
                Correspondence: Ming Cao; Haige Chen Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, People’s Republic of China Email chowming2007@gmail.com; rjbladder@163.com
                [*]

                These authors contributed equally to this work

                Article
                259240
                10.2147/OTT.S259240
                7588836
                © 2020 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, Tables: 5, References: 33, Pages: 10
                Categories
                Original Research

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