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Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

ABSTRACT: During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor cells (CTC) from patients with progressive metastatic solid tumors, with a focus on men with castration-resistant prostate cancer (CRPC) and women with metastatic breast cancer. We showed that the majority (> 80%) of these CTCs in patients with metastatic CRPC coexpress epithelial proteins such as epithelial cell adhesion molecule (EpCAM), cytokeratins (CK), and E-cadherin, with mesenchymal proteins including vimentin, N-cadherin and O-cadherin, and the stem cell marker CD133. Equally, we found that more than 75% of CTCs from women with metastatic breast cancer coexpress CK, vimentin, and N-cadherin. The existence and high frequency of these CTCs coexpressing epithelial, mesenchymal, and stem cell markers in patients with progressive metastases has important implications for the application and interpretation of approved methods to detect CTCs.

SUBMITTER: Armstrong AJ

PROVIDER: S-EPMC3157566 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

Armstrong Andrew J AJ Marengo Matthew S MS Oltean Sebastian S Kemeny Gabor G Bitting Rhonda L RL Turnbull James D JD Herold Christina I CI Marcom Paul K PK George Daniel J DJ Garcia-Blanco Mariano A MA

Molecular cancer research : MCR 20110610 8

During cancer progression, malignant cells undergo epithelial-mesenchymal transitions (EMT) and mesenchymal-epithelial transitions (MET) as part of a broad invasion and metastasis program. We previously observed MET events among lung metastases in a preclinical model of prostate adenocarcinoma that suggested a relationship between epithelial plasticity and metastatic spread. We thus sought to translate these findings into clinical evidence by examining the existence of EMT in circulating tumor c ...[more]

PMID: 21665936

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Project description:The presence of circulating tumor cells (CTC) in breast cancer might be associated with stem cell-like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, to be able to disseminate and metastasize, CTC must be able to perform epithelial-mesenchymal transition (EMT). We studied the expression of three EMT markers and the stem cell marker ALDH1 in CTC from 502 primary breast cancer patients. Data were correlated with the presence of disseminated tumor cells (DTC) in the bone marrow (BM) and with clinicopathological data of the patients.A total of 2 × 5 ml of blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1, HER2 and beta-Actin transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [TWIST1, Akt2, phosphoinositide kinase-3 (PI3K?)] and separately for the tumor stem cell marker ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Two BM aspirates from all patients were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3.Ninety-seven percent of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts, respectively. CTC were detected in 97/502 (19%) patients. At least one of the EMT markers was expressed in 29% and ALDH1 was present in 14% of the samples, respectively. Interestingly, 5% of the ALDH1-positive and 18% of the EMT-positive patients were CTC-negative based on the cut-off level determined for CTC-positivity applying the AdnaTest BreastCancer. DTC in the BM were detected in 107/502 (21%) patients and no correlation was found between BM status and CTC positivity (P = 0.41). The presence of CTC, EMT and ALDH1 expression was not correlated to any of the prognostic clinical markers.Our data indicate that (1) a subset of primary breast cancer patients shows EMT and stem cell characteristics and (2) the currently used detection methods for CTC are not efficient to identify a subtype of CTC which underwent EMT. (3) The clinical relevance on prognosis and therapy response has to be further evaluated in a prospective trial.

Project description:IntroductionEpithelial 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.MethodsThe 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.ResultsAmong 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.ConclusionsCTCs 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.

Project description:BackgroundAlthough circulating tumor cells (CTCs) are considered as a surrogate marker in monitoring disease progression and treatment response in late stage prostate cancer (PCa), its clinical impact in localized PCa remains unclear, indicating the limitation that is simply based on cell count. This perspective observational study aimed to detect the epithelial-to-mesenchymal transition (EMT) subtypes of CTCs in localized PCa and analyze their clinical relevance and application in predicting PCa stages before surgery compared with the Partin table.Patients and methodsBetween August 2017 and April 2019, 80 newly diagnosed localized PCa patients were enrolled in the study. Peripheral blood samples (5 mL) were collected prior to surgery. The CanPatrolTM CTC enrichment technique, a size-based isolation method, was used to detect the EMT CTCs. Clinical relevance of the CTCs was analyzed with Spearman's rank correlation test. Models to predict pathological were built with multivariate logistic regression. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis were performed to evaluate the accuracy of the prediction model.ResultsCTCs were detected in 55% of all patients. The biophenotypic CTCs were most valuable and closely correlated with PSA, Gleason score, D'Amico risk classification, and pathological stage in localized PCa. The mesenchymal subtype was rare in this population but associated with seminal vesicle invasion, while the epithelial subtype had limited clinical significance. In addition, the biophenotypic CTCs combined with traditional clinical variables were analyzed by multivariate logistic regression to predict organ-confined disease before surgery, of which the AUC reached 0.818 and was superior to the Partin table 2017 in our cohort.ConclusionThis study highlights the clinical impact of the biophenotypic CTCs in localized PCa, which was most closely related to clinical variables and could help to predict pathology outcomes before surgery.

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Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

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Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers.

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