Development of a Novel Method to Detect Prostate Cancer Circulating Tumor Cells (CTCs) Based on Epithelial-Mesenchymal Transition Biology

177 Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that commonly arises in later stages of castration resistant prostate cancer (CRPC), especially with visceral metastases in the setting of a low prostate-specific antigen (PSA). The genes AURKA and MYCNare frequently amplified. There are no reliable serum markers to identify patients that are transforming to NEPC and incidence of circulating tumor cells (CTCs) in these patients is unknown. Detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor (AR) targeted therapies. Methods: Ten men with metastatic NEPC underwent metastatic tumor biopsy and blood collection for CTC analysis utilizing the Epic Sciences platform. Clinical characteristics, pathologic and molecular features including exome sequencing of metastatic tumors, serum PSA and neuroendocrine (NE) markers, CTC count by CellSearch were obtained on all patients. AURKA and MYCNamplification were assessed by FISH in both tumors and Epic CTCs. Results: Sites of metastases included liver (6 out of 10), bone (9 out of 10), lymph nodes (8 out of 10), pleura (1 out of 10), and lungs (2 out of 10). Serum PSA, CellSearch CTCs, and serum NE markers were variable including 4 out of 10 patients with PSA less than 1 ng/ml (range 0.02-9.39) and 3 out of 5 evaluated patients with CTC count of zero (range 0 to 94). Four out of 7 evaluated tumors displayed amplification of AURKA and MYCN. Epic CTCs demonstrated frequent clusters, dim/low cytokeratin suggesting epithelial plasticity, and low AR expression. Patients were subsequently treated with platinum (4 out of 10), AURKAinhibitor (4 out of 10), or hormonal therapy (2 out of 10). Conclusions: PSA, serum NE markers, and CTC count by CellSearch may not be reliable in identifying patients with CRPC that have NE features. Epithelial plasticity potentially arising from epithelial-mesenchymal transition may explain lack of detection using conventional CTC assays. The Epic Sciences CTC platform is capable of detecting CTCs from patients with NEPC and CTCs are molecularly similar to metastatic biopsies. Epic CTCs may be useful in the earlier detection of NEPC and inform patient selection for therapy.

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The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

Prostate Cancer ◽

10.1155/2020/7938280 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Tanzila Khan ◽

Kieran F. Scott ◽

Therese M. Becker ◽

John Lock ◽

Mohammed Nimir ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Resistance Mechanisms ◽

Oncogenic Signaling ◽

Mesenchymal Transition ◽

Development Of Resistance ◽

Castrate Resistant

Prostate cancer (PCa) is initially driven by excessive androgen receptor (AR) signaling with androgen deprivation therapy (ADT) being a major therapeutic approach to its treatment. However, the development of drug resistance is a significant limitation on the effectiveness of both first-line and more recently developed second-line ADTs. There is a need then to study AR signaling within the context of other oncogenic signaling pathways that likely mediate this resistance. This review focuses on interactions between AR signaling, the well-known phosphatidylinositol-3-kinase/AKT pathway, and an emerging mediator of these pathways, the Hippo/YAP1 axis in metastatic castrate-resistant PCa, and their involvement in the regulation of epithelial-mesenchymal transition (EMT), a feature of disease progression and ADT resistance. Analysis of these pathways in circulating tumor cells (CTCs) may provide an opportunity to evaluate their utility as biomarkers and address their importance in the development of resistance to current ADT with potential to guide future therapies.

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Hsp27 Regulates Epithelial Mesenchymal Transition, Metastasis, and Circulating Tumor Cells in Prostate Cancer

Cancer Research ◽

10.1158/0008-5472.can-12-3979 ◽

2013 ◽

Vol 73 (10) ◽

pp. 3109-3119 ◽

Cited By ~ 123

Author(s):

Masaki Shiota ◽

Jennifer L. Bishop ◽

Ka Mun Nip ◽

Anousheh Zardan ◽

Ario Takeuchi ◽

...

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition

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Epithelial-Mesenchymal Transition: A Hallmark in Metastasis Formation Linking Circulating Tumor Cells and Cancer Stem Cells

Pathobiology ◽

10.1159/000337106 ◽

2012 ◽

Vol 79 (4) ◽

pp. 195-208 ◽

Cited By ~ 109

Author(s):

Magdalena Ksiazkiewicz ◽

Aleksandra Markiewicz ◽

Anna J. Zaczek

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Metastasis Formation ◽

Mesenchymal Transition

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Development and Validation for Prognostic Nomogram of Epithelial Ovarian Cancer Recurrence based on Circulating Tumor Cells and Epithelial–Mesenchymal Transition

10.21203/rs.3.rs-86051/v2 ◽

2020 ◽

Author(s):

Jiani Yang ◽

Jun Ma ◽

Yue Jin ◽

Shanshan Cheng ◽

Shan Huang ◽

...

Keyword(s):

Ovarian Cancer ◽

Risk Stratification ◽

Epithelial Ovarian Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Ca 125 ◽

Mesenchymal Transition ◽

Cox Regression Analysis ◽

Significant Difference

Abstract We aimed to determine prognosis value of circulating tumor cells(CTCs) undergoing epithelial–mesenchymal transition(EMT) in epithelial ovarian cancer(EOC) recurrence. We used CanPatrol CTC-enrichment technique to detect CTCs from blood samples and classify subpopulations into epithelial, mesenchymal and hybrids. To construct nomogram, prognostic factors were selected by Cox regression analysis. Risk stratification was performed through Kaplan–Meier analysis among training group(n=114) and validation group(n=38). By regression screening, both CTC counts(HR 1.187; 95%CI 1.098-1.752; p=0.012) and M-CTC(HR 1.098; 95%CI 1.047-1.320; p=0.009) were demonstrated as independent factors for recurrence. Other variables including pathological grade, FIGO stage, lymph node metastasis, ascites and CA-125 were also collected(p < 0.005) to construct nomogram. The C-index of internal and external validation for nomogram was 0.913 and 0.874. We found significant predictive value for nomogram with/without CTCs (AUC 0.8705 and 0.8097). Taking CTC counts and M-CTC into separation, the values were 0.8075 and 0.8262. Finally, survival curves of risk stratification based on CTC counts(p=0.0241), M-CTC(p=0.0107) and the nomogram(p=0.0021) were drawn with significant difference. In conclusion, CTCs could serve as a novel factor for EOC prognosis. Nomogram model constructed by CTCs and other clinical parameters could predict EOC recurrence and perform risk stratification for clinical decision-making.Trial registration: Chinese Clinical Trial Registry, ChiCTR-DDD-16009601, October 25, 2016

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Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset

Cancers ◽

10.3390/cancers11040483 ◽

2019 ◽

Vol 11 (4) ◽

pp. 483 ◽

Cited By ~ 37

Author(s):

Chiara Agnoletto ◽

Fabio Corrà ◽

Linda Minotti ◽

Federica Baldassari ◽

Francesca Crudele ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Cell Subset ◽

Intermediate Phenotype ◽

Current Evidence ◽

Early Event ◽

Tumor Type ◽

Mesenchymal Transition ◽

Immunodeficient Mice

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.

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