Oncotarget

Research Papers:

EMT-like circulating tumor cells in ovarian cancer patients are enriched by platinum-based chemotherapy

Issam Chebouti, Sabine Kasimir-Bauer, Paul Buderath, Pauline Wimberger, Siegfried Hauch, Rainer Kimmig and Jan Dominik Kuhlmann _

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Oncotarget. 2017; 8:48820-48831. https://doi.org/10.18632/oncotarget.16179

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Abstract

Issam Chebouti1,4, Sabine Kasimir-Bauer1,4, Paul Buderath1,4, Pauline Wimberger2,3,4, Siegfried Hauch5, Rainer Kimmig1,4 and Jan Dominik Kuhlmann2,3,4

1Department of Gynecology and Obstetrics, University Hospital Essen, 45147 Essen, Germany

2Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany

3National Center for Tumor Diseases (NCT), Partner Site Dresden, 69120 Heidelberg, Germany

4German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

5QIAGEN, 40724 Hilden, Germany

Correspondence to:

Jan Dominik Kuhlmann, email: [email protected]

Keywords: ovarian cancer, circulating tumor cells, epithelial-to-mesenchymal-transition, PI3Kα, Akt-2

Received: January 06, 2017     Accepted: February 27, 2017     Published: March 14, 2017

ABSTRACT

Background: Assuming that tumor cell dissemination requires a shift to a mesenchymal phenotype, we analyzed the incidence of epithelial-to-mesenchymal-transition (EMT)-like circulating tumor cells (CTCs) in ovarian cancer patients and inquired, how their molecular phenotypes respond to platinum-based chemotherapy and influence outcome.

Results: Before surgery, overall detection rate for epithelial CTCs was 18%. EMT-like CTCs were more frequently observed (30%) and were mutually exclusive to epithelial CTCs in the majority of patients (82%). After chemotherapy, EMT-like CTCs increased up to 52%, accompanied by the “de novo” emergence of PI3Kα+/Twist+ EMT-like CTCs. Before surgery, PI3K+ EMT-like CTCs in combination with epithelial CTCs indicated decreased OS (p = 0.02) and FIGO I-III patients with residual tumor burden after surgery were more likely to be positive for EMT-like CTCs after chemotherapy (p = 0.02). In the latter group, epithelial CTCs alone significantly correlated with decreased PFS and OS (p = 0.02, p = 0.002), supported by an additional inclusion of PI3K+ CTCs (OS, p = 0.001).

Materials and Methods: Blood samples of 91 ovarian cancer patients before surgery and 31 matched samples after adjuvant chemotherapy were evaluated for CTCs with the AdnaTest ovarian cancer and EMT-1, analyzing the epithelial-associated transcripts EpCAM, Muc-1 and CA125 and the EMT-associated transcripts PI3Kα, Akt-2 and Twist.

Conclusions: Platinum-based chemotherapy seems to select for EMT-like CTCs in ovarian cancer patients and provokes a shift towards PI3Kα and Twist expressing CTCs, which may reflect clonal tumor evolution towards therapy resistance. It has to be determined, whether this CTC subgroup may serve as a biomarker to identify patients at high risk.


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