Development of a microfluidic device to assess procoagulant activity in ovarian cancer in response to treatment with chemotherapeutic agents


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Kathryn Date1, Yuehua Dou1, Marina Flynn2, Leigh Madden1, John Greenman1
1University of Hull, Hull, UK, 2Castle Hill Hospital, Hull, UK

Background

It is widely appreciated that an increased incidence of venous thromboembolism (VTE) is observed in certain cancers (including ovarian cancer). This is believed to be potentiated by tumour cell-derived microparticles (MP) expressing tissue factor, which acts as the primary initiator of the coagulation cascade. The use of certain chemotherapy drugs has been identified as an independent risk factor for VTE in ovarian cancer patients. The cytotoxic action of chemotherapy drugs is predicted to enhance MP release, thereby directly promoting procoagulant activity. Existing in vivo models of ovarian cancer are acknowledged to have severe limitations. The development of a microfluidic device is intended to provide a more biologically relevant model, allowing the response of the whole tissue sample to be analysed, and a more representative response to the drug treatments to be attained.

Method

The procoagulant potential of MP from established ovarian cancer cell lines was assessed using a pro-thrombin time clotting assay, and the effect of chemotherapy drugs on this response was determined. Spheroid cultures were established from these cell lines and assessed in a similar manner. The viability of ovarian tumour tissue on a previously developed microfluidic tissue device has been studied, and the procoagulant activity of the associated tumour MP monitored via pro-thrombin time and a microfluidic-based impedance sensor.

Results

Treatment with certain chemotherapy drugs was found to further accelerate the clotting of supernatants from drug-sensitive cell lines while, similarly, drug treatment of spheroids established from these cell lines produced faster clotting supernatants. The effluent collected from ovarian tumour tissue samples maintained on a microfluidic device was also found to exhibit procoagulant activity.

Conclusion

In vitro studies suggest that the use of chemotherapy drugs enhances procoagulant activity of ovarian cancer cell lines. A microfluidic platform will provide the appropriate technology for testing this concept directly on ovarian tumours.