Background: Malignant mesothelioma is an aggressive cancer with a low response to current therapies due to the development of chemo-resistance. The use of reliable and clinically relevant model systems is essential for mechanistic studies into the causes of chemo-resistance, as well as for the identification of new treatments. Here we investigate the phenotypic differences between parental II-45 rat mesothelioma cells and chemo-resistant mesothelioma models derived from these cells.
Method: Chemo-resistant cell lines were generated by 15 rounds of exposure to physiologically relevant doses of the current standard of care agents; cisplatin and pemetrexed individually and in combination, gemcitabine and vinorelbine. Normal rat mesothelial cells, the parental and the 5 resulting chemo-resistant mesothelioma cell lines were characterized for resistance to these and other agents. Syngeneic Fischer rats were pleurally engrafted with these cell lines and circulating haematological, cytokine and biomarker profiles were generated, and, survival determined. Tumours arising from these cell lines were assessed by size, morphology, immunohistochemical markers of human malignancy, chromosomal changes and expression of genes involved in drug resistance and metabolism.
Results: The 5 different chemo-resistant II-45 cell lines were approximately 2-fold resistant to the chemotherapeutic agent they were selected against. Tumours derived from both the parental and chemo-resistant cell lines were immunohistochemically indistinct from human mesothelioma. Homozygous deletion of p16INK4A/p14ARF, and increased expression of several ATP-binding cassette transporters and the Androgen receptor were demonstrated, consistent with findings in human mesothelioma. Further, the acquisition of chemo-resistance resulted in changes to tumour morphology, overall survival and increases in plasma levels of growth regulated onocogene/keratinocyte chemo attractant, interleukin 10 and vascular endothelial growth factor.
Conclusion: In conclusion, these models display many features corresponding with the human disease, and provide the first series of matched parental and chemo-resistant models to be used for in vivo mesothelioma studies.