Abstract
BackgroundThe absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible. The claudin proteins are frequently overexpressed in ovarian cancers, but their potential as prognostic, diagnostic, or detection markers remains unclear. Here, we have explored the possible use of these proteins as screening biomarkers for ovarian cancer detection.MethodsClaudin protein shedding from cells was examined by immunoblotting of conditioned culture media. The presence of claudins in exosomes released from ovarian cancer cells was demonstrated by sucrose gradient separation and immunogold electron microscopy experiments. Claudin-4-containing exosomes in the plasma of ovarian cancer patients were evaluated in a pilot panel of 63 ovarian cancer patients and 50 healthy volunteers. The CA125 marker was also assessed in these samples and compared with claudin-4 positivity.ResultsWe show that full-length claudins can be shed from ovarian cancer cells in culture and found in the media as part of small lipid vesicles known as exosomes. Moreover, 32 of 63 plasma samples from ovarian cancer patients exhibited the presence of claudin-4-containing exosomes. In contrast, only one of 50 samples from individuals without cancer exhibited claudin-4-positive exosomes. In our small panel, at a specificity of 98%, the claudin-4 and CA125 tests had sensitivities of 51% and 71%, respectively. The two tests did not appear to be independent and were strongly correlated.ConclusionOur work shows for the first time that claudin-4 can be released from ovarian cancer cells and can be detected in the peripheral circulation of ovarian cancer patients. The development of sensitive assays for the detection of claudin-4 in blood will be crucial in determining whether this approach can be useful, alone or in combination with other screening methods, for the detection of ovarian cancer.
Highlights
The absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible
We show for the first time that intact claudin proteins are released from ovarian cancer cells
In order to test the possibility that claudin proteins may be released from cells, we looked for the presence of claudins in conditioned culture media from ovarian cancer cell lines
Summary
The absence of highly sensitive and specific serum biomarkers makes mass screening for ovarian cancer impossible. We have explored the possible use of these proteins as screening biomarkers for ovarian cancer detection. Among the problems related to ovarian cancer detection is the lack of highly specific and sensitive serum biomarkers. The most clinically useful ovarian cancer biomarker, CA125, has been used to assess response to treatment and monitor recurrence of CA125positive tumors [2], but lacks both sensitivity and specificity required for the efficient detection of ovarian cancer in the general population [3,4]. It has been suggested that combining multiple serum markers may help achieve the sensitivity and specificity required for the screening of ovarian cancer [4,10]. There has been a significant interest in the identification and development of new ovarian cancer markers
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