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

• Published in: Oncotarget 2017-07, Vol.8 (30), p.48820-48831
• Main Authors: Chebouti, Issam, Kasimir-Bauer, Sabine, Buderath, Paul, Wimberger, Pauline, Hauch, Siegfried, Kimmig, Rainer, Kuhlmann, Jan Dominik
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor; Cell Count; Chemotherapy, Adjuvant; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Epithelial-Mesenchymal Transition; Female; Humans; Immunophenotyping; Kaplan-Meier Estimate; Neoplastic Cells, Circulating - pathology; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Phenotype; Platinum - administration & dosage; Prognosis; Research Paper; Twist-Related Protein 1 - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.16179

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. 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). 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. 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.