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      Phenotypic characterization of circulating tumor cells in the peripheral blood of patients with small cell lung cancer

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          Abstract

          Background

          To evaluate the phenotypic heterogeneity of circulating tumor cells (CTCs) based on the expression of proliferative, apoptotic and Epithelial-to-Mesenchymal Transmission (EMT) markers during front-line treatment in patients with small cell lung cancer (SCLC) and to evaluate their clinical relevance.

          Methods

          CTCs from 108 chemotherapy-naïve patients with SCLC were analyzed by double immunofluorescence staining using anti-Ki67, anti-M30, anti-Vimentin along with anti-CKs antibodies. In 83 patients CTCs were also enumerated using the CellSearch.

          Results

          Sequential samples were available from 76 and 48 patients after one-treatment cycle and on disease progression (PD), respectively, for immunofluorescence and from 50 and 36 patients after one-cycle and on PD, respectively, for CellSearch. At baseline, 60.2% of the patients had detectable CTCs by either method. Both proliferative (CK67 +) and non-proliferative (Ki67 -), apoptotic (M30 +) and non-apoptotic (M30 -) as well as EMT (Vim +) CTCs were present in the same patient. Among 22 patients without detectable CTCs by CellSearch, CK +/Ki67 + and CK +/Vim + CTCs could be detected in 6 (27.3%) and 6 (27.3%) patients, respectively. One-chemotherapy cycle reduced both the incidence of detection ( p<0.001) and the absolute number ( p<0.001) of CTCs; conversely, on PD both the incidence of detection and the number of CTCs were significantly increased ( p = 0.002 and p = 0.04, respectively). Multivariate analysis revealed that the increased number of Vim + CTCs at baseline and of non-apoptotic CTCs on PD could be emerged as independent prognostic factors associated with decreased OS( p = 0.009 and p = 0.023, respectively).

          Conclusions

          CK +/Ki67 +, CK +/M30 + and CK +/Vim + CTCs represent distinct subpopulations of CTCs in patients with SCLC, can be detected even in the absence of detectable CTCs by CellSearch; CK +/Ki67 + and CK +/Vim + CTCs are associated with unfavorable clinical outcome.

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          Most cited references 38

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          Circulating tumor cells in patients with breast cancer dormancy.

          The purpose of this study was to test the hypothesis that circulating tumor cells (CTCs) are present in patients many years after mastectomy without evidence of disease and that these CTCs are shed from persisting tumor in patients with breast cancer dormancy. We searched for CTCs in 36 dormancy candidate patients and 26 age-matched controls using stringent criteria for cytomorphology, immunophenotype, and aneusomy. Thirteen of 36 dormancy candidates, 7 to 22 years after mastectomy and without evidence of clinical disease, had CTCs, usually on more than one occasion. Only 1 of 26 controls had a possible CTC (no aneusomy). The statistical difference of these two distributions was significant (exact P = 0.0043). The CTCs in patients whose primary breast cancer was just removed had a half-life measured in 1 to 2.4 hours. The CTCs that are dying must be replenished every few hours by replicating tumor cells somewhere in the tissues. Hence, there appears to be a balance between tumor replication and cell death for as long as 22 years in dormancy candidates. We conclude that this is one mechanism underlying tumor dormancy.
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            Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients

            Introduction Epithelial to mesenchymal transition (EMT) is considered an essential process in the metastatic cascade. EMT is characterised by upregulation of vimentin, Twist, Snail, Slug and Sip1 among others. Metastasis is also associated with the presence of circulating tumour cells (CTCs) and disseminated tumour cells in the blood and bone marrow, respectively, of breast cancer patients, but the expression of EMT markers in these cells has not been reported so far. Methods The expression of Twist and vimentin in CTCs of 25 metastatic and 25 early breast cancer patients was investigated by using double-immunofluorescence experiments in isolated peripheral blood mononuclear cell cytospins using anti-cytokeratin (anti-CK) anti-mouse (A45-B/B3) and anti-Twist or anti-vimentin anti-rabbit antibodies. Results Among early breast cancer patients, vimentin-and Twist-expressing CK+ CTCs were identified in 77% and 73% of the patients, respectively, and in 100% of the patients with metastatic breast cancer for both markers (P = 0.004 and P = 0.037, respectively). Among patients with early disease, 56% and 53% of the CK+ CTCs were double-stained with vimentin and Twist, and the corresponding values for metastatic patients were 74% and 97%, respectively (P = 0.005 and P = 0.0001, respectively). The median expression of CK+vimentin+ and CK+Twist+ cells per patient in metastatic patients was 98% and 100%, and in an adjuvant chemotherapy setting the corresponding numbers were 56% and 40.6%, respectively. Triple-staining experiments revealed that all CK+Twist+ or CK+vimentin+ cells were also CD45-, confirming their epithelial origin. Immunomagnetic separation of CTCs and triple-immunofluorescence with anti-CK/anti-Twist/anti-vimentin antibodies demonstrated that both mesenchymal markers could be coexpressed in the same CK+ cell, since 64% of the total identified CTCs were triple-stained. There was a significant correlation (P = 0.005) between the number of CTCs expressing Twist and vimentin within the same setting. Conclusions CTCs expressing Twist and vimentin, suggestive of EMT, are identified in patients with breast cancer. The high incidence of these cells in patients with metastatic disease compared to early stage breast cancer strongly supports the notion that EMT is involved in the metastatic potential of CTCs.
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              Small-cell lung cancer.

              Small-cell lung carcinoma is an aggressive form of lung cancer that is strongly associated with cigarette smoking and has a tendency for early dissemination. Increasing evidence has implicated autocrine growth loops, proto-oncogenes, and tumour-suppressor genes in its development. At presentation, the vast majority of patients are symptomatic, and imaging typically reveals a hilar mass. Pathology, in most cases of samples obtained by bronchoscopic biopsy, should be undertaken by pathologists with pulmonary expertise, with the provision of additional tissue for immunohistochemical stains as needed. Staging should aim to identify any evidence of distant disease, by imaging of the chest, upper abdomen, head, and bones as appropriate. Limited-stage disease should be treated with etoposide and cisplatin and concurrent early chest irradiation. All patients who achieve complete remission should be considered for treatment with prophylactic cranial irradiation, owing to the high frequency of brain metastases in this disease. Extensive-stage disease should be managed by combination chemotherapy, with a regimen such as etoposide and cisplatin administered for four to six cycles. Thereafter, patients with progressive or recurrent disease should be treated with additional chemotherapy. For patients who survive long term, careful monitoring for development of a second primary tumour is necessary, with further investigation and treatment as appropriate.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 July 2017
                2017
                : 12
                : 7
                Affiliations
                [1 ] Laboratory of Tumor Cell Biology, Medical School, University of Crete, Heraklion, Greece
                [2 ] Department of Medical Oncology, University General Hospital of Heraklion, Crete, Greece
                [3 ] Department of Pathology, University General Hospital of Heraklion, Crete, Greece
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-17-14239
                10.1371/journal.pone.0181211
                5515424
                28719656
                © 2017 Messaritakis et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 1, Tables: 4, Pages: 15
                Product
                Funding
                This work was partly supported by research grants from the Cretan Association for Biomedical Research (CABR) and the Hellenic Society of Medical Oncology (HeSMO).
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Lung and Intrathoracic Tumors
                Small Cell Lung Cancer
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Immunofluorescence
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Biology and Life Sciences
                Genetics
                Phenotypes
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Staining
                Cell Staining
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Staining
                Immunofluorescence Staining
                Custom metadata
                The minimal underlying data set necessary for replication of this study is available within the paper and its Supporting Information files.

                Uncategorized

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