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. 2015 Oct 15;5(11):3363-75.
eCollection 2015.

The added value of circulating tumor cells examination in ovarian cancer staging

Katarina Kolostova  1 , Rafał Matkowski  2 , Marcin Jędryka  2 , Katarzyna Soter  3 , Martin Cegan  4 , Michael Pinkas  1 , Anna Jakabova  1 , Jiri Pavlasek  5 , Jan Spicka  6 , Vladimir Bobek  7
Affiliations

The added value of circulating tumor cells examination in ovarian cancer staging

Katarina Kolostova et al. Am J Cancer Res. .

Abstract

Delayed diagnosis of ovarian cancer (OC) is usually a cause of its high mortality. OC counts for one of the most aggressive gynecological malignancies. Noninvasive biomarkers may be used to help with diagnostic and treatment decisions in OC management. The incidence and clinical significance of occult OC cells (circulating tumor cells-CTCs) in the peripheral blood of patients with newly diagnosed or nondiagnosed OC at the time of surgical intervention were examined in our study. The objective of the study was to isolate and cultivate CTCs in OC patients (mainly stage IIIB-C) by a recently introduced size-based separation method (MetaCell(®)). CTCs were successfully isolated in patients with OC capturing cells with proliferation potential. The cells were enriched in good fitness, which enabled the short term in vitro culture of the CTCs. The CTCs may be used for further downstream applications (e.g. gene expression analysis) even if in the majority of the in vitro CTC cultures no confluence was reached. The CTCs were detected in 77 out of 118 patients (65.2%). CTC positivity was given to the relationship with different disease stage parameters with special focus on CA125 marker levels. The results show that the information on CTC presence may provide new and independent prognosis staging information to the patient description. Several interesting relationships of CA125, age and ascites presence are reported. As shown in our patient sample, patients with ascites tend to have higher CA125 levels, even if the CTCs were not found in the peripheral blood. It suggests that hematogenous dissemination is fully represented by the CTCs while lymphogenic dissemination is represented by elevated CA125. In this context, easy access to CTCs provided by the method applied in our study, both at the time of diagnosis and relapse, may become an increasingly valuable tool in future. This methodology may provide an opportunity for more personalized medicine where treatment for OC may be guided by information from an individual's CTC molecular profile.

Keywords: CA125; CTCs; circulating tumor cells; cultivation; gene expression; in vitro; ovarian cancer.

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Figures

Figure 1
Figure 1
A-D. CTCs captured and cultured on the membrane filter stained by unspecific vital fluorescent nuclear (NucBlueTM) and cytomplastic (CelltrackerTM) stain. The bar represents 10 μm.
Figure 3
Figure 3
DTCs captured on the separating membrane shown immediately after enrichment (A, B) and after 6 days in vitro culture where cells already show differentiation towards epithelial character (C, D). Cells are visualized by CelltrackerTM. The bar represents 20 μm.
Figure 2
Figure 2
CTC captured and cultured on the membrane filter with visualized nucleus counterstained with vital nuclear (NucBlueTM) and cytoplasmatic (CelltrackerTM) stain. A. CTC isolated from a patient with diagnosed Clear Cell Ovarian Carcinoma. B. CTC isolated from a patient with Serous Ovarian Carcinoma. The bar represents 10 μm.
Figure 4
Figure 4
Cluster analysis of the clinicopathological criteria of OC-patients involved into this type f analysis. A. Cluster analysis without CA125 as variable. B. Cluster analysis including CA125 (elevation of CA125 is reported in relative numbers 1 (elevated) and 0 (normal)).
Figure 5
Figure 5
Means of absolute CA125 values (U/ml) are shown for different clinicopathological groups on the graph. The data show that the CA125 elevated levels are correlated to more serious disease characteristics (lymph node involvement, peritoneal carcinomatosis, ascites presence, residual disease presence), but not exclusively to the CTC-positivity. As shown CTC and CA125 are independent biomarkers in our group of OC patients.
Figure 6
Figure 6
Absolute CA125 values (U/ml) in groups with CTC presence/absence and CA125-specification.
Figure 7
Figure 7
FIGO stages and absolute CA125 levels (U/ml). The data displayed on the graph show, that absolute CA125 levels do not correlate with FIGO stages. Elevated CA125 levels are typical to the FIGO IIIB stage (a blue column). FIGO IIIB is characterized by microscopic and macroscopic pelvic cancer mass presence. On the other site CA125 (U/ml) levels are associated with ascites presence (P<0.05). Taken together elevated CA125 could characterize peritoneal spread of the OC. CTCs were not seen more frequently at IIIB.
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