Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma

Sci Rep. 2014 Aug 21;4:6152. doi: 10.1038/srep06152.

Abstract

Mesothelioma is inherently chemo-resistant with only 50% of patients responding to the standard of care treatments, and consequently it has a very grim prognosis. The aim of this study was to establish a panel of chemo-resistant mesothelioma models with clinically relevant levels of resistance as tools for investigating chemo-resistance and identifying new treatments for mesothelioma. Chemo-resistant cell lines were established in vitro and characterized in vivo using syngeneic Fischer rats. Tumors derived from all chemo-resistant cell lines were immunohistochemically classified as mesothelioma. Homozygous deletion of p16(INK4A)/p14(ARF) and increased expression of several ATP-binding cassette transporters were demonstrated, consistent with findings in human mesothelioma. Further, the acquisition of chemo-resistance in vitro resulted in changes to tumor morphology and overall survival. In conclusion, these models display many features corresponding with the human disease, and provide the first series of matched parental and chemo-resistant models for in vitro and in vivo mesothelioma studies.

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cytokines / blood
  • Cytokines / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Glutathione / metabolism
  • Inhibitory Concentration 50
  • Lymphocyte Count
  • Mesothelioma / drug therapy
  • Mesothelioma / genetics*
  • Mesothelioma / immunology
  • Mesothelioma / metabolism
  • Mesothelioma / mortality
  • Mesothelioma / pathology
  • Multigene Family
  • Phenotype
  • Rats

Substances

  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cytokines
  • Glutathione