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Zhuang Y, Su K, Liu S, Fan W, Lv H, Zhong W. Clinical significances of RPL15 gene expression in circulating tumor cells of patients with breast cancer. Biomed Rep 2025; 22:82. [PMID: 40151798 PMCID: PMC11948298 DOI: 10.3892/br.2025.1960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 02/12/2025] [Indexed: 03/29/2025] Open
Abstract
The preferred biomarkers for evaluating the outcomes of patients with breast cancer (BC) remain poorly understood. The present study aimed to investigate the predictive roles of circulating tumor cells (CTCs) and ribosomal protein L 15 (RPL15) expression in the prognosis of patients with BC. A total of 170 patients were included in the present study, all of whom were female. BC was diagnosed by combining clinical features, imaging and pathological findings. CanPatrol™ technology and triple color in situ RNA hybridization were used to detect CTC subtypes and RPL15 gene expression levels. CTCs were classified into epithelial CTCs, mesenchymal CTCs (MCTCs), and hybrid CTCs (HCTCs) according to cellular surface markers. Risk factors for recurrence and metastasis were validated by a multivariate COX regression model. Kaplan-Meier survival curves were used to determine the progression-free survival (PFS) of patients. The results showed that patients with advanced tumor-node-metastasis stage and triple negative BC had high MCTCs, HCTCs and RPL15 levels (P<0.05). Furthermore, the multivariate COX regression analysis revealed that MCTCs, HCTCs, HER2+ and positive RPL15 gene expression were key factors for recurrence and metastasis of patients (P<0.05). The PFS of patients with >2 MCTCs/5 ml blood, >5 HCTCs/5 ml blood, and positive RPL15 gene expression in CTCs were significantly shorter than that of patient with 2 MCTCs, 5 HCTCs, and negative RPL15 gene expression in CTCs (P<0.05). By contrast, the PFS of patients with positive HER2 also was significantly shorter than that of patients with negative HER2. Overall, the present data indicated that the PFS of patients with BC with >2 MCTC or >5 HCTCs, and positive RPL15 gene expression was shorter than that of those with 2 MCTCs or 5 HCTCs, and negative RPL15 gene expression. Additionally, the prognosis of patients with BC with negative HER2 is more favorable than the prognosis of patients with positive HER2 expression.
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Affiliation(s)
- Ying Zhuang
- Breast Cancer Center, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, P.R. China
- National Key Clinical Specialty Discipline Construction Program, Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
- Wuhan Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
| | - Keli Su
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Shushu Liu
- Breast Cancer Center, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, P.R. China
- National Key Clinical Specialty Discipline Construction Program, Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
- Wuhan Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
| | - Wei Fan
- Breast Cancer Center, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, P.R. China
- National Key Clinical Specialty Discipline Construction Program, Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
- Wuhan Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
| | - Huijuan Lv
- Department of Oncology, The Fourth People's Hospital of Jinan, Jinan, Shandong 250031, P.R. China
| | - Wei Zhong
- Breast Cancer Center, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, P.R. China
- National Key Clinical Specialty Discipline Construction Program, Hubei Provincial Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
- Wuhan Clinical Research Center for Breast Cancer, Wuhan, Hubei 430079, P.R. China
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Extracellular Vesicles as Biomarkers in Head and Neck Squamous Cell Carcinoma: From Diagnosis to Disease-Free Survival. Cancers (Basel) 2023; 15:cancers15061826. [PMID: 36980712 PMCID: PMC10046514 DOI: 10.3390/cancers15061826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/14/2023] [Accepted: 03/15/2023] [Indexed: 03/22/2023] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) arising from different anatomical sites present with different incidences and characteristics, which requires a personalized treatment strategy. Despite the extensive research that has conducted on this malignancy, HNSCC still has a poor overall survival rate. Many attempts have been made to improve the outcomes, but one of the bottlenecks is thought to be the lack of an effective biomarker with high sensitivity and specificity. Extracellular vesicles (EVs) are secreted by various cells and participate in a great number of intercellular communications. Based on liquid biopsy, EV detection in several biofluids, such as blood, saliva, and urine, has been applied to identify the existence and progression of a variety of cancers. In HNSCC, tumor-derived EVs exhibit many functionalities by transporting diverse cargoes, which highlights their importance in tumor screening, the determination of multidisciplinary therapy, prediction of prognosis, and evaluation of therapeutic effects. This review illustrates the classification and formation of EV subtypes, the cargoes conveyed by these vesicles, and their respective functions in HNSCC cancer biology, and discloses their potential as biomarkers during the whole process of tumor diagnosis, treatment, and follow-up.
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Zhao Q, Li B, Gao Q, Luo Y, Ming L. Prognostic value of epithelial–mesenchymal transition circulating tumor cells in female breast cancer: A meta-analysis. Front Oncol 2022; 12:1024783. [DOI: 10.3389/fonc.2022.1024783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/07/2022] [Indexed: 12/05/2022] Open
Abstract
BackgroundEpithelial–mesenchymal transition (EMT) conferred metastatic properties on circulating tumor cells (CTCs) and was considered to be correlated with bad survival outcomes in patients with breast cancer. However, different studies have reported controversial results regarding the relationship between CTCs that have undergone EMT (EMT-CTCs) and prognosis of breast cancer. Therefore, this meta-analysis aimed to investigate the prognostic role of EMT-CTCs in patients with breast cancer.MethodsIn total, 842 patients from nine studies that were screened from Web of Science, Embase, and PubMed were included. The hazard ratio (HR) and 95% confidence interval (CI) for progression-free survival (PFS) and overall survival (OS) were extracted or estimated by the Kaplan–Meier survival curve for the meta-analysis. Sensitivity analysis was performed to characterize heterogeneity among the trials. Meanwhile, subgroup analysis was performed to present the effects of cancer stage, identification method, sampling volume, and region on the prognostic value of EMT-CTCs.ResultsThe pooled HRs for PFS were 1.97 (univariate: 95% CI, 1.19–3.24; p = 0.008) and 2.23 (multivariate: 95% CI, 1.29–3.86; p = 0.004). The pooled HRs for OS were 2.03 (univariate: 95% CI, 1.07–3.84; p = 0.029) and 1.70 (multivariate: 95% CI, 1.14–2.52; p = 0.009). Subgroup analysis showed that EMT-CTCs were associated with PFS in the primary breast cancer group (pooled HR = 2.58, 95% CI, 1.66–4.00, p < 0.001), the polymerase chain reaction (PCR) group (pooled HR = 2.69, 95% CI, 1.66–4.35, p < 0.001), the sampling volume of the >7.5-ml group (pooled HR = 1.93, 95% CI, 1.36–2.73, p < 0.001), and the Asia group (pooled HR = 1.92, 95% CI, 1.13–3.29, p = 0.017) and with OS in the primary breast cancer group (pooled HR = 3.59, 95% CI, 1.62–7.95; p = 0.002).ConclusionThe meta-analysis showed that EMT-CTCs were associated with poorer survival outcomes in patients with breast cancer. More accurate methods and designed clinical trials with unified standards are essential to establish the real role of EMT-CTCs in disease progression in women with breast cancer.
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Okabe T, Togo S, Fujimoto Y, Watanabe J, Sumiyoshi I, Orimo A, Takahashi K. Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy. Cancers (Basel) 2020; 12:E3588. [PMID: 33266262 PMCID: PMC7761066 DOI: 10.3390/cancers12123588] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/22/2022] Open
Abstract
Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial-mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine.
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Affiliation(s)
- Takahiro Okabe
- Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Shinsaku Togo
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yuichi Fujimoto
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Junko Watanabe
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Issei Sumiyoshi
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Akira Orimo
- Departments of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Kazuhisa Takahashi
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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Mego M, Kalavska K, Karaba M, Minarik G, Benca J, Sedlackova T, Gronesova P, Cholujova D, Pindak D, Mardiak J, Celec P. Plasma Nucleosomes in Primary Breast Cancer. Cancers (Basel) 2020; 12:cancers12092587. [PMID: 32927889 PMCID: PMC7563724 DOI: 10.3390/cancers12092587] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/03/2020] [Accepted: 09/08/2020] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Nucleosomes composed of DNA and histone proteins enter the extracellular space and end eventually in the circulation when cells die. In blood plasma, they could represent a nonspecific marker of cell death, potentially useful for noninvasive monitoring of cancer. The aim of this study was to analyze circulating nucleosomes in relation to patient/tumor characteristics and prognosis in nonmetastatic breast cancer. This study included 92 patients with breast cancer treated with surgery. Plasma nucleosomes were detected in samples taken in the morning on the day of surgery. Circulating nucleosomes were positively associated with the systemic inflammation but not with other patient/tumor characteristics. Patients with lower nucleosomes had lower risk of disease recurrence compared to patients with higher nucleosomes. Our data suggest that plasma nucleosomes in nonmetastatic breast cancer are associated with systemic inflammation and might have a prognostic value. The underlying mechanisms require further studies. Abstract When cells die, nucleosomes composed of DNA and histone proteins enter the extracellular space and end eventually in the circulation. In plasma, they might serve as a nonspecific marker of cell death, potentially useful for noninvasive monitoring of tumor dynamics. The aim of this study was to analyze circulating nucleosomes in relation to patient/tumor characteristics and prognosis in primary breast cancer. This study included 92 patients with breast cancer treated with surgery for whom plasma isolated was available in the biobank. Plasma nucleosomes were detected in samples taken in the morning on the day of surgery using Cell Death Detection ELISA kit with anti-histone and anti-DNA antibodies. Circulating nucleosomes were positively associated with the systemic inflammatory index (SII), but not with other patient/tumor characteristics. Patients with high SII in comparison to low SII had higher circulating nucleosomes (by 59%, p = 0.02). Nucleosomes correlated with plasma plasminogen activator inhibitor-1, IL-15, IL-16, IL-18, and hepatocyte growth factor. Patients with lower nucleosomes had significantly better disease-free survival (HR = 0.46, p = 0.05). In a multivariate analysis, nucleosomes, hormone receptor status, HER2 status, lymph node involvement, and tumor grade were independent predictors of disease-free survival. Our data suggest that plasma nucleosomes in primary breast cancer are associated with systemic inflammation and might have a prognostic value. The underlying mechanisms require further studies.
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Affiliation(s)
- Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 83310 Bratislava, Slovakia;
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 83310 Bratislava, Slovakia;
- Correspondence: or ; Tel.: +421-2-59378366; Fax: +421-2-54774943
| | - Katarina Kalavska
- Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 83310 Bratislava, Slovakia;
| | - Marian Karaba
- Department of Oncosurgery, National Cancer Institute, 83310 Bratislava, Slovakia; (M.K.); (J.B.); (D.P.)
| | - Gabriel Minarik
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81372 Bratislava, Slovakia; (G.M.); (T.S.); (P.C.)
| | - Juraj Benca
- Department of Oncosurgery, National Cancer Institute, 83310 Bratislava, Slovakia; (M.K.); (J.B.); (D.P.)
- Department of Medicine, St. Elizabeth University, 81102 Bratislava, Slovakia
| | - Tatiana Sedlackova
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81372 Bratislava, Slovakia; (G.M.); (T.S.); (P.C.)
| | - Paulina Gronesova
- Biomedical Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia; (P.G.); (D.C.)
| | - Dana Cholujova
- Biomedical Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia; (P.G.); (D.C.)
| | - Daniel Pindak
- Department of Oncosurgery, National Cancer Institute, 83310 Bratislava, Slovakia; (M.K.); (J.B.); (D.P.)
- Department of Oncosurgery, Slovak Medical University, 83101 Bratislava, Slovakia
| | - Jozef Mardiak
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 83310 Bratislava, Slovakia;
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 81372 Bratislava, Slovakia; (G.M.); (T.S.); (P.C.)
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Bian J, Yan K, Liu N, Xu X. Correlations between circulating tumor cell phenotyping and 18F-fluorodeoxyglucose positron emission tomography uptake in non-small cell lung cancer. J Cancer Res Clin Oncol 2020; 146:2621-2630. [PMID: 32661602 DOI: 10.1007/s00432-020-03244-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 05/04/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE The epithelial-to-mesenchymal transition (EMT) phenotype-based subsets of circulating tumor cells (CTCs) might be predictors of tumor progression. We evaluated the clinical properties of different phenotypic CTCs in patients with non-small cell lung cancer (NSCLC). Secondly, we explored the association between different phenotypic CTCs and the uptake of 18F-fluorodeoxyglucose (FDG) by the primary tumor on a positron emission tomographic (PET) scan. METHODS Venous blood samples from 34 pathologically confirmed Stage IIB-IVB NSCLC patients were collected prospectively. CTCs were immunoassayed using a SE-i·FISH®CTC kit. We identified CTCs into cytokeratin positive (CK+) and cytokeratin negative (CK-) phenotypes. CTC classifications were correlated with the maximum standardized uptake value (SUVmax) measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). Overall survival (OS) and progression-free survival (PFS) curves were produced using the Kaplan-Meier method. RESULTS CTCs were detected in 91.2% of NSCLC patients. CTC counting was associated with TNM stage (P = 0.014) and distant metastasis (P = 0.007). The number of CK-CTCs was also positively associated with TNM stage (P = 0.022) and distant metastasis (P = 0.007). Both total CTC counting and CK-CTC counting did not show association with SUVmax value (P = 0.959, P = 0.903). Kaplan-Meier survival analysis demonstrated that patients with ≥ 7 CTCs had shorter OS (P = 0.003) and PFS (P = 0.001) relative to patients with < 7 CTCs). Notably, the number of CK-CTCs can act as independent risk factors for PFS (P = 0.044) and OS (P = 0.043) in NSCLC patients. However, SUVmax value was not associated with OS (P = 0.895) and PFS (P = 0.686). CONCLUSION The CTC subpopulations could be useful evidence for testing metastasis and prognosis in NSCLC patients. The SUVmax value of the primary tumor was not related to prognosis in patients with NSCLC.
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Affiliation(s)
- Jiarong Bian
- Department of Respiratory Medicine, Northern Jiangsu Province Hospital, Clinical Medical College of Yangzhou University, 28 Nan Tong Road, Yangzhou, 225001, People's Republic of China
| | - Ke Yan
- Department of Neurosurgery, Northern Jiangsu Province Hospital, Clinical Medical College of Yangzhou University, Yangzhou, 225001, People's Republic of China
| | - Na Liu
- Department of Respiratory Medicine, Northern Jiangsu Province Hospital, Clinical Medical College of Yangzhou University, 28 Nan Tong Road, Yangzhou, 225001, People's Republic of China
| | - Xingxiang Xu
- Department of Respiratory Medicine, Northern Jiangsu Province Hospital, Clinical Medical College of Yangzhou University, 28 Nan Tong Road, Yangzhou, 225001, People's Republic of China.
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Inflammation-Based Scores Increase the Prognostic Value of Circulating Tumor Cells in Primary Breast Cancer. Cancers (Basel) 2020; 12:cancers12051134. [PMID: 32369910 PMCID: PMC7281016 DOI: 10.3390/cancers12051134] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/16/2020] [Accepted: 04/29/2020] [Indexed: 12/26/2022] Open
Abstract
A correlation between circulating tumor cells (CTCs) and monocytes in metastatic breast cancer (BC), where CTCs and monocyte-to-lymphocyte ratio (MLR) were predictors of overall survival (OS), was recently shown. Herein, we aimed to assess the association between CTCs and the complete blood count (CBC)-derived inflammation-based scores in 284 primary BC patients. CTCs were determined in CD45-depleted peripheral blood mononuclear cells by real time-PCR. This method allowed us to detect a subset of CTCs with an epithelial-to-mesenchymal transition phenotype (CTC EMT), previously associated with inferior outcomes in primary BC. In the present study, CTC EMT positivity (hazard ratio (HR) = 2.4; 95% CI 1.20–4.66, p = 0.013) and elevated neutrophil-to-lymphocyte ratio (NLR) (HR = 2.20; 95% CI 1.07–4.55; p = 0.033) were associated with shorter progression-free survival (PFS) in primary BC patients. Multivariate analysis showed that CTC EMT-positive patients with NLR ≥ 3 had 8.6 times increased risk of disease recurrence (95% CI 2.35–31.48, p = 0.001) compared with CTC EMT-negative patients with NLR < 3. Similarly, disease recurrence was 13.14 times more likely in CTC EMT-positive patients with MLR ≥ 0.34 (95% CI 4.35–39.67, p < 0.001). Given its low methodological and financial demands, the CBC-derived inflammation-based score determination could, after broader validation, significantly improve the prognostication of BC patients.
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Hu B, Tian X, Li Y, Liu Y, Yang T, Han Z, An J, Kong L, Li Y. Epithelial-mesenchymal transition may be involved in the immune evasion of circulating gastric tumor cells via downregulation of ULBP1. Cancer Med 2020; 9:2686-2697. [PMID: 32077634 PMCID: PMC7163085 DOI: 10.1002/cam4.2871] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/24/2022] Open
Abstract
Background Increasing numbers of studies have demonstrated that circulating tumor cells (CTCs) undergo a phenotypic change termed epithelial‐mesenchymal transition (EMT), and researchers have proposed that EMT might provide CTCs with increased potential to survive in the different microenvironments encountered during metastasis through various ways, such as by increasing cell survival and early colonization. However, the exact role of EMT in CTCs remains unclear. Methods In this study, we identified CTCs of 41 patients with gastric cancer using Cyttel‐CTC and im‐FISH (immune‐fluorescence in situ hybridization) methods, and tested the expression of EMT markers and ULBP1 (a major member of the NKG2D—natural killer [NK] group 2 member D—ligand family) on CTCs. Moreover, we investigated the relationship between the expression of EMT markers and ULBP1 on CTCs and gastric cancer cell lines. Results Our results showed that the CTCs of gastric cancer patients exhibited three EMT marker subtypes, and that the expression of ULBP1 was significantly lower on mesenchymal phenotypic CTCs (M+CTCs) than on epithelial phenotypic CTCs (E+CTCs). EMT induced by TGF‐β in vitro produced a similar phenomenon, and we therefore proposed that EMT might be involved in the immune evasion of CTCs from NK cells by altering the expression of ULBP1. Conclusions Our study indicated that EMT might play a vital role in the immune invasion of CTCs by regulating the expression of ULBP1 on CTCs. These findings could provide potential strategies for targeting the immune evasion capacity of CTCs.
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Affiliation(s)
- Baoguang Hu
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Xiaokun Tian
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China.,Department of Burn and Plastic Surgery, the Sixth People's Hospital of Zibo, Zibo, China
| | - Yanbin Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yangchun Liu
- Jiangxi Medical College, Queen Mary College of Nanchang University, Nanchang, China
| | - Tao Yang
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Zhaodong Han
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Jiajia An
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, China
| | - Lingqun Kong
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Yuming Li
- Department of Gastrointestinal Surgery, Binzhou Medical University Hospital, Binzhou, China
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Ito M, Horimoto Y, Tokuda E, Murakami F, Uomori T, Himuro T, Nakai K, Orihata G, Iijima K, Saito M. Impact of circulating tumour cells on survival of eribulin-treated patients with metastatic breast cancer. Med Oncol 2019; 36:89. [PMID: 31520329 DOI: 10.1007/s12032-019-1314-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 09/06/2019] [Indexed: 12/21/2022]
Abstract
Several clinical studies have examined circulating tumour cells (CTCs). However, the application of CTCs as a predictive/prognostic marker for breast cancer patients has yet to be established, particularly the selection of suitable markers for detecting CTCs. We recently investigated CTCs, including mesenchymal status, from metastatic breast cancer patients who had received eribulin-based treatment. We found that assessment of both mesenchymal and epithelial CTCs might be important for predicting eribulin responsiveness. In the current study, we followed up the outcomes of these patients after eribulin treatment and investigated the possibility of CTC analysis results serving as prognostic markers for this patient population. Twenty-one patients were enrolled and peripheral blood samples were collected before eribulin-based treatments. CTCs were then examined using a Microfluidic Chip device. CTCs positive for vimentin and pan-cytokeratin were defined as mesenchymal and epithelial CTCs, respectively. Overall survival (OS) was assessed in relation to the number of CTCs and clinicopathological factors. During the observation period, 13 patients (62%) died due to breast cancer and the median OS was 18 months. Patients with high-grade tumours and a high total number of CTCs showed significantly shorter OS than those with low-grade tumours and smaller CTC burdens (p = 0.026 and 0.037, respectively). Patients who received eribulin as the first chemotherapy for metastatic disease showed longer OS (p = 0.006). Our data suggest that determining numbers of both mesenchymal and epithelial CTCs might predict survival for patients receiving eribulin.
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Affiliation(s)
- Mayuko Ito
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Yoshiya Horimoto
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Emi Tokuda
- Department of Medical Oncology, Fukushima Medical University, 1 Hikariga-oka, Fukushima City, Fukushima, 960-1295, Japan
| | - Fumi Murakami
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Toshitaka Uomori
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takanori Himuro
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Katsuya Nakai
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Gotaro Orihata
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kotaro Iijima
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Mitsue Saito
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
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Thery L, Meddis A, Cabel L, Proudhon C, Latouche A, Pierga JY, Bidard FC. Circulating Tumor Cells in Early Breast Cancer. JNCI Cancer Spectr 2019; 3:pkz026. [PMID: 31360902 PMCID: PMC6649836 DOI: 10.1093/jncics/pkz026] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 02/24/2019] [Accepted: 03/27/2019] [Indexed: 12/25/2022] Open
Abstract
Circulating tumor cells (CTCs) are particularly rare in non-metastatic breast cancer, and the clinical validity of CTC detection in that clinical setting was initially not well recognized. A cytological CTC detection device (CellSearch) fulfilling the CLIA requirements for analytical validity was subsequently developed and, in 2008, we reported the first study (REMAGUS02) showing that distant metastasis-free survival was shorter in early breast cancer patients with one or more CTCs. In the past 10 years, other clinical studies and meta-analyses have established CTC detection as a level-of-evidence 1 prognostic biomarker for local relapses, distant relapses, and overall survival. This review summarizes available data on CTC detection and the promises of this proliferation- and subtype-independent metastasis-associated biomarker in early breast cancer patients.
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Affiliation(s)
- Laura Thery
- Department of Medical Oncology, Institut Curie, Paris and Saint Cloud, France
| | | | - Luc Cabel
- Department of Medical Oncology, Institut Curie, Paris and Saint Cloud, France.,Circulating Tumor Biomarkers Laboratory, Institut Curie, Inserm CIC 1428, PSL Research University, Paris, France.,UVSQ, Paris Saclay University, Saint Cloud, France
| | - Charlotte Proudhon
- Circulating Tumor Biomarkers Laboratory, Institut Curie, Inserm CIC 1428, PSL Research University, Paris, France
| | - Aurelien Latouche
- Inserm U900, Institut Curie, Saint Cloud, France.,Conservatoire national des arts et métiers, Paris, France
| | - Jean-Yves Pierga
- Department of Medical Oncology, Institut Curie, Paris and Saint Cloud, France.,Circulating Tumor Biomarkers Laboratory, Institut Curie, Inserm CIC 1428, PSL Research University, Paris, France.,Université Paris Descartes, Paris, France
| | - Francois-Clement Bidard
- Department of Medical Oncology, Institut Curie, Paris and Saint Cloud, France.,Circulating Tumor Biomarkers Laboratory, Institut Curie, Inserm CIC 1428, PSL Research University, Paris, France.,UVSQ, Paris Saclay University, Saint Cloud, France
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11
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Mittal V. Epithelial Mesenchymal Transition in Tumor Metastasis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:395-412. [PMID: 29414248 DOI: 10.1146/annurev-pathol-020117-043854] [Citation(s) in RCA: 970] [Impact Index Per Article: 161.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment. However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results. Therefore, determining the functional role of EMT in metastasis remains an area of active investigation. Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis. This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities.
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Affiliation(s)
- Vivek Mittal
- Department of Cardiothoracic Surgery, Department of Cell and Developmental Biology, and Neuberger Berman Foundation Lung Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA;
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12
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Profiling of Invasive Breast Carcinoma Circulating Tumour Cells-Are We Ready for the 'Liquid' Revolution? Cancers (Basel) 2019; 11:cancers11020143. [PMID: 30691008 PMCID: PMC6406427 DOI: 10.3390/cancers11020143] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 12/24/2022] Open
Abstract
As dissemination through blood and lymph is the critical step of the metastatic cascade, circulating tumour cells (CTCs) have attracted wide attention as a potential surrogate marker to monitor progression into metastatic disease and response to therapy. In patients with invasive breast carcinoma (IBC), CTCs are being considered nowadays as a valid counterpart for the assessment of known prognostic and predictive factors. Molecular characterization of CTCs using protein detection, genomic and transcriptomic panels allows to depict IBC biology. Such molecular profiling of circulating cells with increased metastatic abilities appears to be essential, especially after tumour resection, as well as in advanced disseminated disease, when information crucial for identification of therapeutic targets becomes unobtainable from the primary site. If CTCs are truly representative of primary tumours and metastases, characterization of the molecular profile of this easily accessible ‘biopsy’ might be of prime importance for clinical practice in IBC patients. This review summarizes available data on feasibility and documented benefits of monitoring of essential IBC biological features in CTCs, with special reference to multifactorial proteomic, genomic, and transcriptomic panels of known prognostic or predictive value.
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13
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Zhao XH, Wang ZR, Chen CL, Di L, Bi ZF, Li ZH, Liu YM. Molecular detection of epithelial-mesenchymal transition markers in circulating tumor cells from pancreatic cancer patients: Potential role in clinical practice. World J Gastroenterol 2019; 25:138-150. [PMID: 30643364 PMCID: PMC6328963 DOI: 10.3748/wjg.v25.i1.138] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) patients.
METHODS We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule (EpCAM) (E-CTC), the mesenchymal cell markers vimentin and twist (M-CTC), or both (E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.
RESULTS CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage (P < 0.01) and distant metastasis (P < 0.01). Additionally, lymphocyte counts and NLR in patients without CTCs were significantly different from those in patients testing positive for each CTC subpopulation (P < 0.01).
CONCLUSION Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.
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Affiliation(s)
- Xiao-Hui Zhao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zai-Rui Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Chang-Long Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Ling Di
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zhuo-Fei Bi
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Zhi-Hua Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Yi-Min Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
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14
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Horimoto Y, Tokuda E, Murakami F, Uomori T, Himuro T, Nakai K, Orihata G, Iijima K, Togo S, Shimizu H, Saito M. Analysis of circulating tumour cell and the epithelial mesenchymal transition (EMT) status during eribulin-based treatment in 22 patients with metastatic breast cancer: a pilot study. J Transl Med 2018; 16:287. [PMID: 30342534 PMCID: PMC6195982 DOI: 10.1186/s12967-018-1663-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/12/2018] [Indexed: 01/02/2023] Open
Abstract
Background Liquid biopsy approaches, such as measuring circulating tumour cells (CTCs), have recently been introduced in several clinical studies. However, the development of CTCs as a predictive marker for treatment effects on breast cancer remains an enormous task. We investigated CTCs, including epithelial mesenchymal transition (EMT) status, from metastatic breast cancer patients who had received eribulin-based treatment, which reportedly suppresses EMT as a means of tumour suppression. Our aim was to test the possibility of this method serving as a tool predicting eribulin efficacy. Methods Twenty-two patients were enrolled and peripheral blood samples were collected before eribulin treatment. CTCs were then examined using a Microfluidic Chip device. CTCs positive for vimentin and pan-cytokeratin were defined as mesenchymal and epithelial CTCs, respectively. Progression-free survival (PFS) and clinical response were assessable in 20 and 18 patients, respectively, in relation to the number of CTCs. Results Numbers of total CTCs were significantly increased in patients with progressive disease during treatment (p = 0.006). Median PFS was 14.6 weeks and patients with more total and mesenchymal CTCs at baseline had significantly shorter PFS (p = 0.0013 and 0.013, respectively). Multivariate logistic regression analysis revealed small number of total baseline CTCs and long disease-free survival to be related to long PFS (p = 0.0004 and 0.020, respectively). Conclusions Our data suggest that determining both mesenchymal and epithelial CTCs at baseline might be a good tool for predicting eribulin responsiveness. Evaluation of mesenchymal CTC can be considered as a parameter in larger studies, while most clinical trials are currently employing only the detection of the epithelial cellular adhesion molecule (EpCAM). Electronic supplementary material The online version of this article (10.1186/s12967-018-1663-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yoshiya Horimoto
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. .,Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
| | - Emi Tokuda
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Fumi Murakami
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Toshitaka Uomori
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Takanori Himuro
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Katsuya Nakai
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Gotaro Orihata
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Kotaro Iijima
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Shinsaku Togo
- Department of Respiratory Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Hideo Shimizu
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Mitsue Saito
- Department of Breast Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
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15
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Riethdorf S, O'Flaherty L, Hille C, Pantel K. Clinical applications of the CellSearch platform in cancer patients. Adv Drug Deliv Rev 2018; 125:102-121. [PMID: 29355669 DOI: 10.1016/j.addr.2018.01.011] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 01/12/2018] [Accepted: 01/15/2018] [Indexed: 12/29/2022]
Abstract
The CellSearch® system (CS) enables standardized enrichment and enumeration of circulating tumor cells (CTCs) that are repeatedly assessable via non-invasive "liquid biopsy". While the association of CTCs with poor clinical outcome for cancer patients has clearly been demonstrated in numerous clinical studies, utilizing CTCs for the identification of therapeutic targets, stratification of patients for targeted therapies and uncovering mechanisms of resistance is still under investigation. Here, we comprehensively review the current benefits and drawbacks of clinical CTC analyses for patients with metastatic and non-metastatic tumors. Furthermore, the review focuses on approaches beyond CTC enumeration that aim to uncover therapeutically relevant antigens, genomic aberrations, transcriptional profiles and epigenetic alterations of CTCs at a single cell level. This characterization of CTCs may shed light on the heterogeneity and genomic landscapes of malignant tumors, an understanding of which is highly important for the development of new therapeutic strategies.
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16
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Associations between the Epithelial-Mesenchymal Transition Phenotypes of Circulating Tumor Cells and the Clinicopathological Features of Patients with Colorectal Cancer. DISEASE MARKERS 2017; 2017:9474532. [PMID: 29430076 PMCID: PMC5752983 DOI: 10.1155/2017/9474532] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 11/02/2017] [Indexed: 12/17/2022]
Abstract
In this study, we identified CTCs using the previously reported CanPatrol CTC enrichment technique from peripheral blood samples of 126 patients with colorectal cancer (CRC) and found that CTCs could be classified into three subpopulations based on expression of epithelial cell adhesion molecule (EpCAM) (E-CTCs), the mesenchymal cell marker vimentin (M-CTCs), or both EpCAM and vimentin (biphenotypic E/M-CTCs). Circulating tumor microemboli (CTMs) were also identified in peripheral blood samples. Meanwhile, E-CTCs, M-CTCs, E/M-CTCs, and CTMs were detected in 76.98%, 42.06%, 56.35%, and 36.51% of the 126 patients, respectively. Interestingly, the presence of CTMs and each CTC subpopulation was significantly associated with blood lymphocyte counts and tumor-node-metastasis stage (P < 0.001). Lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) in patients lacking CTCs were significantly different from those in patients testing positive for CTMs and each CTC subpopulation (P < 0.001). Our results indicate that tumor metastasis is more significantly associated with the presence of CTMs and M-CTCs than with other CTC subpopulations and suggest that EMT may be involved in CTC evasion of lymphocyte-mediated clearance.
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17
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Škovierová H, Okajčeková T, Strnádel J, Vidomanová E, Halašová E. Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis (Review). Int J Mol Med 2017; 41:1187-1200. [PMID: 29286071 PMCID: PMC5819928 DOI: 10.3892/ijmm.2017.3320] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 11/23/2017] [Indexed: 12/13/2022] Open
Abstract
Numerous studies over the past two decades have focused on the epithelial-to-mesenchymal transition (EMT) and its role in the development of metastasis. Certain studies highlighted the importance of EMT in the dissemination of tumor cells and metastasis of epithelium-derived carcinomas. Tumor metastasis is a multistep process during which tumor cells change their morphology, and start to migrate and invade distant sites. The present review discusses the current understanding of the molecular mechanisms contributing to EMT in embryogenesis, fibrosis and tumorigenesis. Additionally, the signaling pathways that initiate EMT through transcriptional factors responsible for the activation and suppression of various genes associated with cancer cell migration were investigated. Furthermore, the important role of the epigenetic modifications that regulate EMT and the reverse process, mesenchymal-to-epithelial transition (MET) are discussed. MicroRNAs are key regulators of various intracellular processes and current knowledge of EMT has significantly improved due to microRNA characterization. Their effect on signaling pathways and the ensuing events that occur during EMT at the molecular level is becoming increasingly recognized. The current review also highlights the role of circulating tumor cells (CTCs) and CTC clusters, and their ability to form metastases. In addition, the biological properties of different types of circulating cells based on their tumor-forming potential are compared.
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Affiliation(s)
- Henrieta Škovierová
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Terézia Okajčeková
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Ján Strnádel
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Eva Vidomanová
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Erika Halašová
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
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18
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Bredemeier M, Kasimir-Bauer S, Kolberg HC, Herold T, Synoracki S, Hauch S, Edimiris P, Bankfalvi A, Tewes M, Kimmig R, Aktas B. Comparison of the PI3KCA pathway in circulating tumor cells and corresponding tumor tissue of patients with metastatic breast cancer. Mol Med Rep 2017; 15:2957-2968. [PMID: 28358430 PMCID: PMC5428904 DOI: 10.3892/mmr.2017.6415] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/19/2016] [Indexed: 12/16/2022] Open
Abstract
The aim of the present study was to compare the phosphatidylinositol 3-kinase (PI3KCA)-AKT serine/threonine kinase (AKT) pathway in circulating tumor cells (CTCs) and corresponding cancerous tissues. Stemness-like circulating tumor cells (slCTCs) and CTCs in epithelial-mesenchymal transition (EMT) have been implicated as the active source of metastatic spread in breast cancer (BC). In this regard, the PI3KCA-AKT signaling pathway was demonstrated to be implicated in and to be frequently mutated in BC. The present study compared this pathway in slCTCs/CTCs in EMT and the corresponding tumor tissues of 90 metastatic BC patients (pts). slCTCs and CTCs in EMT were isolated using the AdnaTest EMT-1/StemCell for the detection of aldehyde dehydrogenase 1 family member A1 (ALDH1) (singleplex PCR) and PI3KCA, AKT2 and twist family bHLH transcription factor 1 (multiplex PCR). Tumor tissue was investigated for PI3KCA hotspot mutations using Sanger sequencing of genomic DNA from micro-dissected formalin-fixed paraffin-embedded tissue, and for the expression of ALDH1 and phosphorylated AKT (pAKT), and phosphatase and tensin homolog (PTEN) loss, by immunohistochemistry. slCTCs were identified in 23% of pts (21/90 pts) and CTCs in EMT in 56% (50/90 pts) of pts. pAKT and ALDH1 positivity in tumor tissue was identified in 47 and 9% of cases, respectively, and a PTEN loss was observed in 18% of pts. A significant association was detected between pAKT expression in cancerous tissue and AKT2 expression in CTCs (P=0.037). PI3KCA mutations were detected in 32% of pts, most frequently on exons 21 (55%) and 10 (45%). Pts with PI3KCA mutations in tumor tissue had a significantly longer overall survival than pts with wild-type PI3KCA expression (P=0.007). Similar results were obtained for pts with aberrant PI3KCA signaling in CTCs and/or aberrant signaling in cancerous tissue (P=0.009). Therapy-resistant CTCs, potentially derived from the primary tumor or metastatic tissue, may be eliminated with specific PI3K pathway inhibitors, alone or in combination, to improve the prognosis of metastatic BC pts.
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Affiliation(s)
- Maren Bredemeier
- Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Sabine Kasimir-Bauer
- Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Hans-Christian Kolberg
- Department of Gynecology and Obstetrics, Marienhospital Bottrop, D‑46236 Bottrop, Germany
| | - Thomas Herold
- Institute of Pathology, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Sarah Synoracki
- Institute of Pathology, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | | | - Philippos Edimiris
- Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Agnes Bankfalvi
- Institute of Pathology, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Mitra Tewes
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Rainer Kimmig
- Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
| | - Bahriye Aktas
- Department of Gynecology and Obstetrics, University Hospital Essen, University of Duisburg‑Essen, D‑45122 Essen, Germany
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19
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Multi-Phenotypic subtyping of circulating tumor cells using sequential fluorescent quenching and restaining. Sci Rep 2016; 6:33488. [PMID: 27647345 PMCID: PMC5028835 DOI: 10.1038/srep33488] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 08/23/2016] [Indexed: 01/06/2023] Open
Abstract
In tissue biopsies formalin fixed paraffin embedded cancer blocks are micro-sectioned producing multiple semi-identical specimens which are analyzed and subtyped proteomically, and genomically, with numerous biomarkers. In blood based biopsies (BBBs), blood is purified for circulating tumor cells (CTCs) and clinical utility is typically limited to cell enumeration, as only 2–3 positive fluorescent markers and 1 negative marker can be used. As such, increasing the number of subtyping biomarkers on each individual CTC could dramatically enhance the clinical utility of BBBs, allowing in depth interrogation of clinically relevant CTCs. We describe a simple and inexpensive method for quenching the specific fluors of fluorescently stained CTCs followed by sequential restaining with additional biomarkers. As proof of principle a CTC panel, immunosuppression panel and stem cell panel were used to sequentially subtype individual fluorescently stained patient CTCs, suggesting a simple and universal technique to analyze multiple clinically applicable immunomarkers from BBBs.
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20
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Shaaban S, Alsulami M, Arbab SA, Ara R, Shankar A, Iskander A, Angara K, Jain M, Bagher-Ebadian H, Achyut BR, Arbab AS. Targeting Bone Marrow to Potentiate the Anti-Tumor Effect of Tyrosine Kinase Inhibitor in Preclinical Rat Model of Human Glioblastoma. ACTA ACUST UNITED AC 2016; 12:69-81. [PMID: 27429653 DOI: 10.3923/ijcr.2016.69.81] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Antiangiogenic agents caused paradoxical increase in pro-growth and pro-angiogenic factors and caused tumor growth in glioblastoma (GBM). It is hypothesized that paradoxical increase in pro-angiogenic factors would mobilize Bone Marrow Derived Cells (BMDCs) to the treated tumor and cause refractory tumor growth. The purposes of the studies were to determine whether whole body irradiation (WBIR) or a CXCR4 antagonist (AMD3100) will potentiate the effect of vatalanib (a VEGFR2 tyrosine kinase inhibitor) and prevent the refractory growth of GBM. Human GBM were grown orthotopically in three groups of rats (control, pretreated with WBIR and AMD3100) and randomly selected for vehicle or vatalanib treatments for 2 weeks. Then all animals underwent Magnetic Resonance Imaging (MRI) followed by euthanasia and histochemical analysis. Tumor volume and different vascular parameters (plasma volume (vp), forward transfer constant (Ktrans), back flow constant (kep), extravascular extracellular space volume (ve) were determined from MRI. In control group, vatalanib treatment increased the tumor growth significantly compared to that of vehicle treatment but by preventing the mobilization of BMDCs and interaction of CXCR4-SDF-1 using WBIR and ADM3100, respectively, paradoxical growth of tumor was controlled. Pretreatment with WBIR or AMD3100 also decreased tumor cell migration, despite the fact that ADM3100 increased the accumulation of M1 and M2 macrophages in the tumors. Vatalanib also increased Ktrans and ve in control animals but both of the vascular parameters were decreased when the animals were pretreated with WBIR and AMD3100. In conclusion, depleting bone marrow cells or CXCR4 interaction can potentiate the effect of vatalanib.
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Affiliation(s)
- S Shaaban
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - M Alsulami
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - S A Arbab
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - R Ara
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - A Shankar
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - A Iskander
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - K Angara
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - M Jain
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - H Bagher-Ebadian
- Department of Radiology, Henry Ford Health System, Detroit, MI, USA
| | - B R Achyut
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
| | - A S Arbab
- Laboratory of Tumor Angiogenesis, Department of Biochemistry and Molecular Biology, Cancer Center, Georgia Regents University, Augusta, GA, 30912, USA
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Cermeño EA, García AJ. Tumor-Initiating Cells: Emerging Biophysical Methods of Isolation. CURRENT STEM CELL REPORTS 2016; 2:21-32. [PMID: 27141429 PMCID: PMC4851112 DOI: 10.1007/s40778-016-0036-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The discovery and subsequent isolation of tumor-initiating cells (TICs), a small population of highly tumorigenic and drug-resistant cancer cells also called cancer stem cells (CSCs), have revolutionized our understanding of cancer. TICs are isolated using various methodologies, including selection of surface marker expression, ALDH activity, suspension culture, and chemotherapy/drug resistance. These methods have several drawbacks, including their variability, lack of robustness and scalability, and low specificity. Alternative methods of purification take advantage of biophysical properties of TICs including their adhesion and stiffness. This review will provide a brief overview of TIC biology as well as review the most important methods of TIC isolation with a focus on biophysical methods of TIC purification.
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Affiliation(s)
- Efraín A. Cermeño
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA
| | - Andrés J. García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA
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22
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Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, Bhattacharya S, Basu A. Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep 2016. [PMID: 26906973 DOI: 10.1038/srep21903%2010.1038/srep21903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
In cancer progression, proteolytic enzymes like serine proteases and metalloproteinases degrade the basement membrane enabling the tumor cells to invade the adjacent tissues. Thus, invasion and metastasis are augmented by these enzymes. Simultaneous silencing of uPA and MMP9 in breast cancer cells decreased the wound healing, migratory, invasive and adhesive capacity of the cells. After simultaneous down regulation, cells were seen to be arrested in the cell cycle. There was a remarkable increase in the expression of cell to cell adhesion molecule E-cadherin, and decrease in Vimentin and Snail expression. In addition, there was a significant decrease in the expression of the stem cell marker Oct-4. In the breast tumor samples it has been observed that, tumors, expressing higher level of uPA and MMP9, express less amount of E-cadherin. It has also been observed that few tumors also show, Vimentin positive in the ductal epithelial area. Thus, our model can help for checking the aggressive tumor invasion by blocking of uPA and MMP9. Our present observations also give the concept of the presence of aggressive epithelial cells with mesenchymal nature in the tumor micro-environment, altering the expression of EMT genes.
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Affiliation(s)
- Anuradha Moirangthem
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
| | - Banashree Bondhopadhyay
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
| | - Mala Mukherjee
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Arghya Bandyopadhyay
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Narendranath Mukherjee
- Department of Surgery, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Karabi Konar
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Shubham Bhattacharya
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Anupam Basu
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
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23
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Moirangthem A, Bondhopadhyay B, Mukherjee M, Bandyopadhyay A, Mukherjee N, Konar K, Bhattacharya S, Basu A. Simultaneous knockdown of uPA and MMP9 can reduce breast cancer progression by increasing cell-cell adhesion and modulating EMT genes. Sci Rep 2016; 6:21903. [PMID: 26906973 PMCID: PMC4764826 DOI: 10.1038/srep21903] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 01/28/2016] [Indexed: 11/09/2022] Open
Abstract
In cancer progression, proteolytic enzymes like serine proteases and metalloproteinases degrade the basement membrane enabling the tumor cells to invade the adjacent tissues. Thus, invasion and metastasis are augmented by these enzymes. Simultaneous silencing of uPA and MMP9 in breast cancer cells decreased the wound healing, migratory, invasive and adhesive capacity of the cells. After simultaneous down regulation, cells were seen to be arrested in the cell cycle. There was a remarkable increase in the expression of cell to cell adhesion molecule E–cadherin, and decrease in Vimentin and Snail expression. In addition, there was a significant decrease in the expression of the stem cell marker Oct-4. In the breast tumor samples it has been observed that, tumors, expressing higher level of uPA and MMP9, express less amount of E–cadherin. It has also been observed that few tumors also show, Vimentin positive in the ductal epithelial area. Thus, our model can help for checking the aggressive tumor invasion by blocking of uPA and MMP9. Our present observations also give the concept of the presence of aggressive epithelial cells with mesenchymal nature in the tumor micro-environment, altering the expression of EMT genes.
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Affiliation(s)
- Anuradha Moirangthem
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
| | - Banashree Bondhopadhyay
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
| | - Mala Mukherjee
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Arghya Bandyopadhyay
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Narendranath Mukherjee
- Department of Surgery, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Karabi Konar
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Shubham Bhattacharya
- Department of Pathology, Burdwan Medical College and Hospital, BurdwanWest Bengal 713104, India
| | - Anupam Basu
- Molecular Biology and Human Genetics Laboratory, Department of Zoology, The University of Burdwan, Golapbag, Burdwan 713104, West Bengal, India
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24
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Mego M, Cholujova D, Minarik G, Sedlackova T, Gronesova P, Karaba M, Benca J, Cingelova S, Cierna Z, Manasova D, Pindak D, Sufliarsky J, Cristofanilli M, Reuben JM, Mardiak J. CXCR4-SDF-1 interaction potentially mediates trafficking of circulating tumor cells in primary breast cancer. BMC Cancer 2016; 16:127. [PMID: 26896000 PMCID: PMC4759765 DOI: 10.1186/s12885-016-2143-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 02/08/2016] [Indexed: 11/14/2022] Open
Abstract
Background Cytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients. Methods This study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays. Results CTCs were detected in 25.2 % patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6 % patients, while CTCs co-expressing both markers were detected in 2.0 % patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2. Conclusion Using cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.
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Affiliation(s)
- M Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University, Klenova 1, 833 10, Bratislava, Slovak Republic. .,Translational Research Unit, Faculty of Medicine, Comenius University, Bratislava, Slovakia. .,National Cancer Institute, Bratislava, Slovakia.
| | - D Cholujova
- National Cancer Institute, Bratislava, Slovakia.
| | - G Minarik
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - T Sedlackova
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - P Gronesova
- Cancer Research Institute, Slovak Academy of Sciences, Slovak Medical University, Bratislava, Slovakia.
| | - M Karaba
- National Cancer Institute, Bratislava, Slovakia.
| | - J Benca
- National Cancer Institute, Bratislava, Slovakia.
| | - S Cingelova
- National Cancer Institute, Bratislava, Slovakia.
| | - Z Cierna
- Department of Pathology, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - D Manasova
- Translational Research Unit, Faculty of Medicine, Comenius University, Bratislava, Slovakia. .,National Cancer Institute, Bratislava, Slovakia.
| | - D Pindak
- National Cancer Institute, Bratislava, Slovakia. .,Slovak Medical University, Bratislava, Slovakia.
| | - J Sufliarsky
- 2nd Department of Oncology, Faculty of Medicine, Comenius University, Klenova 1, 833 10, Bratislava, Slovak Republic. .,National Cancer Institute, Bratislava, Slovakia.
| | - M Cristofanilli
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
| | - J M Reuben
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center Houston, Houston, TX, USA.
| | - J Mardiak
- 2nd Department of Oncology, Faculty of Medicine, Comenius University, Klenova 1, 833 10, Bratislava, Slovak Republic. .,National Cancer Institute, Bratislava, Slovakia.
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25
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Bidard FC, Proudhon C, Pierga JY. Circulating tumor cells in breast cancer. Mol Oncol 2016; 10:418-30. [PMID: 26809472 PMCID: PMC5528978 DOI: 10.1016/j.molonc.2016.01.001] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/12/2015] [Accepted: 01/04/2016] [Indexed: 01/06/2023] Open
Abstract
Over the past decade, technically reliable circulating tumor cell (CTC) detection methods allowed the collection of large datasets of CTC counts in cancer patients. These data can be used either as a dynamic prognostic biomarker or as tumor material for “liquid biopsy”. Breast cancer appears to be the cancer type in which CTC have been the most extensively studied so far, with level‐of‐evidence‐1 studies supporting the clinical validity of CTC count in both early and metastatic stage. This review summarizes and discusses the clinical results obtained in breast cancer patients, the issues faced by the molecular characterization of CTC and the biological findings about cancer biology and metastasis that were obtained from CTC.
In metastatic breast cancer, CTC count is a level‐of‐evidence 1 prognostic dynamic biomarker. Several interventional trials are ongoing to demonstrate the clinical utility of CTC detection in metastatic breast cancer. In early breast cancer, CTC count is also a prognostic biomarker, not correlated with the other usual prognostic factors. Molecular characterization of CTC is promising, trials with anti‐HER2 therapy are ongoing.
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Affiliation(s)
- Francois-Clement Bidard
- Institut Curie, PSL Research University, SiRIC, Laboratory of Circulating Tumor Biomarkers, Paris, France; Institut Curie, PSL Research University, Department of Medical Oncology, Paris, France
| | - Charlotte Proudhon
- Institut Curie, PSL Research University, SiRIC, Laboratory of Circulating Tumor Biomarkers, Paris, France
| | - Jean-Yves Pierga
- Institut Curie, PSL Research University, SiRIC, Laboratory of Circulating Tumor Biomarkers, Paris, France; Institut Curie, PSL Research University, Department of Medical Oncology, Paris, France; Université Paris Descartes, Paris, France.
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