Epithelial tumor cells can become mesenchymal cells and vice versa via phenotypic transitions, a process known as epithelial plasticity. We postulate that during the process of metastasis, circulating tumor cells (CTCs) lose their epithelial phenotype and acquire a mesenchymal phenotype that may not be sufficiently captured by existing epithelial-based CTC technologies. We report here on the development of a novel CTC capture method, based on the biology of epithelial plasticity, which isolates cells based on OB-cadherin cell surface expression. Using this mesenchymal-based assay, OB-cadherin cellular events are detectable in men with metastatic prostate cancer and are less common in healthy volunteers. This method may complement existing epithelial-based methods and may be particularly usefulin patients with bone metastases.
"In three patients , we were able to confirm the malignant origin of these circulating cells by AR FISH . These events could either represent a biologically distinct sub - type associated with an epithelial - mesenchymal transition ( Bitting et al , 2013 ) or traditional CTC with weaker CK staining because of a technical limitation or imaging artifact . Further studies are required to confirm the nature of these CK - weak / negative circulating cells . "
[Show abstract][Hide abstract] ABSTRACT: Background:
Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in CTCs in patients treated with enzalutamide and abiraterone.
CTCs were captured and characterised using the CellSearch system. An automated algorithm to identify CTCs and quantify AR expression was employed. The primary aim was to evaluate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide.
AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients. We observed large intra-patient heterogeneity of AR expression in CTCs. Prior exposure to abiraterone or enzalutamide was not associated with a change in CTCs AR expression (median intensity and distribution of AR-positive classes). In support of this, we also confirmed maintained nuclear AR expression in tissue samples collected after progression on abiraterone. AR staining also identified additional AR-positive CD45-negative circulating cells that were CK-negative/weak and therefore missed using standard protocols. The number of these events correlated with traditional CTCs and was associated with worse outcome on univariate analysis.
We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome.
British Journal of Cancer 02/2015; 112(7). DOI:10.1038/bjc.2015.63 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lung cancer is the leading cause of cancer-related deaths in the United States and worldwide. This has led to major research initiatives focusing on improving early diagnosis rate, as well as the development of pharmacodynamic biomarkers. However, broad clinical integration of these approaches is limited due to the invasive nature of lung biopsies, needle aspirates and resections. Recently, an advance for sampling suspicious lung nodules to collect mini-bronchoalveolar lavage (mBAL) samples was shown to be diagnostically relevant but limited by standard cytology techniques leading to low sensitivity and specificity. In addition, a second non-invasive method that holds great promise is the collection of circulating tumor cells, a rare population of tumor cells that have shed into peripheral circulation from primary or metastatic tumor sites, from blood. Here, we utilize a recently published platform, VerIFAST, for the capture and proteomic analysis of rare cells, to isolate cells of interest from lung cancer patients using both mBAL and blood samples. The VerIFAST platform leverages surface tension at the microscale to pin aqueous and oil fluids in adjacent chambers to create a virtual filter between two aqueous fluids. In this manuscript, the VerIFAST was further enhanced to include oil pinning, which allowed on-device tumbling, further eliminating a laborious and time consuming step that could result in increased sample loss. Finally, we further developed the base assays used in standard histopathologic assays for diagnostic and pharmacodynamic analysis of these rare lung cancer cells. Specifically, we examined thyroid transcription factor-1 (TTF-1) signal intensity, in which loss is associated with more aggressive disease, and epidermal growth factor receptor (EGFR) signal intensity, which is a high value therapeutic target in lung cancer.
Lab on a Chip 10/2013; 14(1). DOI:10.1039/c3lc50912e · 6.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The availability of new therapeutic options for the treatment of metastatic castration-resistant prostate cancer (mCRPC) has heightened the importance of monitoring and assessing treatment response. Accordingly, there is an unmet clinical need for reliable biomarkers that can be used to guide therapy. Circulating tumour cells (CTCs) are rare cells that are shed from primary and metastatic tumour deposits into the peripheral circulation, and represent a means of performing noninvasive tumour sampling. Indeed, enumeration of CTCs before and after therapy has shown that CTC burden correlates with prognosis in patients with mCRPC. Moreover, studies have demonstrated the potential of molecular analysis of CTCs in monitoring and predicting response to therapy in patients. This Review describes the challenges associated with monitoring treatment response in mCRPC, and the advancements in CTC-analysis technologies applied to such assessments and, ultimately, guiding prostate cancer treatment.
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