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

Our plain-English summary of Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma, by A.L. Hudson, C. Weir, E. Moon, et al (Scientific Reports, 2014).

The study

• Authors: A.L. Hudson, C. Weir, E. Moon, R. Harvie, S. Klebe, S.J. Clarke, N. Pavlakis, V.M. Howell
• Journal: Scientific Reports
• Published: 2014;4:6152
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study established and characterised a panel of chemotherapy-resistant rat mesothelioma models. From the rat mesothelioma line II-45 (control: non-malignant mesothelial 4/4 RM.4), five resistant lines were produced by 15 treatment cycles at the 50% growth-inhibition dose of cisplatin, pemetrexed, cisplatin plus pemetrexed, gemcitabine or vinorelbine. Parental II-45 cells were 20-fold more resistant to paclitaxel (p less than 0.001) and 3-fold more resistant to vinorelbine (p less than 0.01) than the non-malignant cells. Abcb1a and Abcg2 transporter genes were greatly elevated in parental II-45 cells; verapamil, a general ABC transporter inhibitor, significantly increased sensitivity of vinorelbine-resistant cells to vinorelbine and pemetrexed-resistant cells to pemetrexed. Homozygous deletion of Cdkn2a/2b, together with co-deletion of Mtap, was found in parental and combination-resistant cells. In Fischer rats, the tumours examined (three per cell line) were all classified immunohistochemically as mesothelioma; pemetrexed-resistant tumours were almost exclusively sarcomatoid with increased podoplanin, and rats given these cells reached the euthanasia endpoint at day 11, earlier than rats given parental cells, while pleural tumour scale did not differ statistically. The authors concluded the models resemble human mesothelioma and suit drug screening.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Experimental laboratory study: in vitro derivation of chemo-resistant cell lines with in vivo characterisation in syngeneic rats
• Who was studied: Rat mesothelioma cell line II-45 and the non-malignant rat mesothelial line 4/4 RM.4, plus female Fischer 344 rats (150-200 g) engrafted into the pleural cavity (n at least 4 per group); work done in Australia
• Exposure: Repeated cycles of chemotherapy drugs: cisplatin, pemetrexed, cisplatin plus pemetrexed, gemcitabine and vinorelbine, each at its IC50 dose for 72 hours, repeated 15 times
• Main results:
  • Parental II-45 mesothelioma cells were 20-fold more resistant to paclitaxel and 3-fold more resistant to vinorelbine than the non-malignant 4/4 RM.4 mesothelial cells, but equally sensitive to cisplatin and gemcitabine and more sensitive to methotrexate
  • After 15 treatment cycles each new cell line showed a statistically significant increase in resistance to the drug it was selected against, and cross-resistance to other drug classes was seen; pemetrexed-resistant cells showed the broadest cross-resistance
  • The drug transporter genes Abcb1a and Abcg2 were greatly raised in parental II-45 cells compared with the non-malignant control cells, and these increases were kept or increased further in the five resistant lines
  • Verapamil, used as an ABC transporter protein inhibitor, significantly increased sensitivity of vinorelbine-resistant cells to vinorelbine (p less than 0.05) and of pemetrexed-resistant cells to pemetrexed (p less than 0.01)
  • Glutathione inhibition with BSO reduced cisplatin resistance in CisR and ComboR cells but the change did not reach statistical significance
  • Comparative genomic hybridization found homozygous deletion of Cdkn2a/2b along with co-deletion of Mtap at 5q32 in both parental and combination-resistant II-45 cells; no abnormalities were found at Nf2, Tp53, Bap1 or Egfr
  • Rats engrafted with pemetrexed-resistant cells reached the ethical endpoint of euthanasia at day 11, significantly earlier than rats with parental II-45 cells (p less than 0.05); pleural tumour scale did not differ statistically between groups
  • Tumour morphology differed by resistant line, from epithelioid for gemcitabine-resistant tumours to almost exclusively sarcomatoid for pemetrexed-resistant and combination-resistant tumours; parental tumours were sarcomatoid with focal epithelioid areas
  • Tumours derived from all chemo-resistant cell lines were immunohistochemically classified as mesothelioma
  • Three tumours per cell line were assessed with the antibody panel, and all were negative for the carcinoma-related markers TTF-1 and CD15
  • Podoplanin was positive in all tumours, with increased expression in tumours derived from pemetrexed-resistant cells
  • In rats bearing parental II-45 tumours, total lymphocytes and CD4, B and NK subsets were significantly decreased while monocytes and the neutrophil to lymphocyte ratio were elevated, compared with healthy control rats
• The authors' conclusion: The authors concluded that the models show many features matching human mesothelioma and provide the first matched parental and chemo-resistant series for in vitro and in vivo study and for screening new treatments
• Limitations the authors state:
  • The authors note the acquired resistance levels in their cells were relatively low
  • Because tumours were started by engraftment, tumorigenesis could not be assessed in these models
  • Few antibodies recognising rat antigens are available, limiting the immunohistochemical panel
  • It is unknown whether the morphological changes with acquired resistance also occur in patients, since post-chemotherapy biopsy is not standard care

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Homozygous Deletion, Overall Survival.

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