Novel ex vivo ovarian cancer tissue explant assay for prediction of chemosensitivity and response to novel therapeutics

The majority of ovarian cancer patients present with advanced disease and despite aggressive treatment, prognosis remains poor. Response to first-line carboplatin-containing chemotherapy is usually good, however, recurrence rates and subsequent chemoresistance are very high and ultimately responsibl...

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Bibliographic Details
Published in:Cancer letters 2018-05, Vol.421, p.51-58
Main Authors: Ricciardelli, Carmela, Lokman, Noor A., Sabit, Ilhamjan, Gunasegaran, Kavyadharshini, Bonner, Wendy M., Pyragius, Carmen E., Macpherson, Anne M., Oehler, Martin K.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Assaying
Carboplatin
Caspase
Caspase-3
Cell culture
Chemoresistance
Chemotherapy
Cryopreservation
Drug Resistance, Neoplasm - drug effects
Drug Screening Assays, Antitumor - methods
Extracellular matrix
Ex vivo explant assay
Female
Humans
Hyaluronic acid
Immunohistochemistry
Medical prognosis
Medical treatment
Metastases
Metastasis
Ovarian cancer
Ovarian carcinoma
Ovarian Neoplasms
Patients
Proliferation
Surgery
Tissue Culture Techniques - methods
Tissues
Tumor cells
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Summary:The majority of ovarian cancer patients present with advanced disease and despite aggressive treatment, prognosis remains poor. Response to first-line carboplatin-containing chemotherapy is usually good, however, recurrence rates and subsequent chemoresistance are very high and ultimately responsible for the fatal outcome of the disease. To improve treatment outcomes pre-clinical models that can predict individual patient response to 1st line chemotherapy and novel therapeutics are urgently required. In this study, we employed an ex vivo ovarian cancer tissue explant assay to assess response to carboplatin and an inhibitor of the extracellular matrix molecule, hyaluronan (4-methylubelliferone, 4-MU), shown to inhibit cancer metastasis. Cryopreserved ovarian cancer tissues were cultured on gelatine sponges for 48–120 h with increasing concentrations of carboplatin (0–400 μM) or 4-MU (1 mM) alone or the combination of both drugs. Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively. The ex vivo tissue explant assay maintained viable tumor cells in an intact tumor microenvironment similar to the in vivo situation over the 120 h culture period. Carboplatin treatment promoted apoptosis in chemosensitive (P = 0.0047) but not chemoresistant cancer tissues. The combination of 4-MU (1 mM) and carboplatin (100 μM) significantly increased apoptosis (P = 0.0111) and reduced proliferation (P = 0.0064) in chemoresistant tissues. Overall, our results show that the ex vivo explant assay is a robust and cost effective model to assess chemosensitivity and the effect of novel therapeutics in ovarian cancer. •We have developed a novel ex vivo explant assay to assess drug response using cryopreserved ovarian cancer tissue.•The ex vivo tissue explant assay maintained an intact tumor microenvironment over the 120 hour culture period.•Carboplatin treatment promoted apoptosis in chemosensitive but not chemoresistant cancer tissues.•Apoptosis was increased in chemoresistant tissues following combined treatment with hyaluronan inhibitor and carboplatin.•Developed a robust and cost effective model to assess chemosensitivity of novel therapeutics in ovarian cancer.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2018.02.006