Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed

Our plain-English summary of Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed, by L. Cortes-Dericks, G.L. Carboni, R.A. Schmid, et al (International Journal of Oncology, 2010).

The study

• Authors: L. Cortes-Dericks, G.L. Carboni, R.A. Schmid, G. Karoubi
• Journal: International Journal of Oncology
• Published: 2010;37(2):437-44
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a lethal cancer of the mesothelium with high chemotherapeutic resistance via unknown mechanisms. A prevailing hypothesis states that cancer stem cells (CSCs) persist in tumors causing relapse after chemotherapy, thus, rendering these cells as critical targets responsible for tumor resistance and recurrence. We selected candidate CSC markers based on expansion under hypoxic conditions, a hallmark for the selection of chemoresistant cells; and investigated the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in three MPM cell lines and normal mesothelial cells by quantitative RT-PCR. Furthermore, we evaluated the chemotherapeutic resistance associated with each CSC marker by determining the change in CSC marker-mRNA levels as an index of drug-resistance following treatment with either cisplatin or pemetrexed. We demonstrate the expression of CSC markers: CD133, Bmi-1, uPAR and ABCG2 in both normal and MPM cell lines. Bmi-1+, uPAR+ and ABCG2+ cells show a distinct role in conferring chemoresistance to cisplatin and pemetrexed in the malignant setting. By contrast, these markers have no apparent participation in chemoresistance to drug treatments in normal mesothelial cells. Intriguingly, CD133 revealed chemoresistant properties in both normal mesothelial and malignant pleural mesothelioma cells. This study provides evidence of putative CSCs conferring drug-resistance to cisplatin and pemetrexed in MPM cell lines. Specific targeting of these drug-resistant cells, while considering the functional heterogeneity of the MPM subtypes, may contribute to more focused and effective chemotherapeutic regimens for malignant pleural mesothelioma.

In plain English

This was a laboratory study of cells grown in dishes, not of patients, and it did not examine asbestos exposure. Researchers in Berne, Switzerland, used three malignant pleural mesothelioma cell lines (H28, H2052 and MSTO211H) and one non-malignant pleural mesothelial cell line (MeT5A). They measured the genetic message (mRNA) for proposed 'cancer stem cell' markers, including Bmi-1, uPAR, ABCG2 and CD133. Bmi-1, uPAR and CD133 were higher in the mesothelioma lines than in the normal line. Low oxygen raised ABCG2, CD133 and uPAR in the mesothelioma lines. The cells were then treated with the chemotherapy drugs cisplatin or pemetrexed, and rises in marker levels were taken as a sign of drug resistance. Responses differed by cell line and drug. For example, in H28 cells cisplatin raised uPAR (p=0.002) and ABCG2 (p=0.02) but lowered CD133 (p=0.04). In the normal line, both drugs raised CD133. The authors concluded that their results suggest putative drug-resistant cancer stem cells exist in the three mesothelioma cell lines, and that the degree of resistance depends on the drug and the mesothelioma subtype.

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: Laboratory (in vitro) cell-line experiment measuring mRNA levels of candidate cancer stem cell markers by quantitative RT-PCR, under low oxygen and after drug treatment
• Who was studied: Three commercially obtained malignant pleural mesothelioma cell lines (H28, H2052, MSTO211H) and the non-malignant human pleural mesothelial cell line MeT5A as a control; work done at University Hospital Berne, Switzerland. No patients were studied.
• Exposure: Not asbestos. The cells were exposed to low oxygen (1% O2 for 48 h) and to single-agent cisplatin or pemetrexed for 48 h at each cell line's IC50 dose, followed by 48 h of recovery. The cisplatin doses were 16, 8, 1 and 0.3 micromolar for H28, H2052, MSTO211H and MeT5A. The pemetrexed doses were 100 micromolar for H28 and H2052, 5 micromolar for MSTO211H and 0.5 micromolar for MeT5A.
• Main results:
  • At baseline, Bmi-1 mRNA was about 5-12 fold higher in the mesothelioma cell lines than in MeT5A.
  • At baseline, uPAR mRNA was 4-8 fold higher in the mesothelioma cell lines than in MeT5A.
  • Under low oxygen, ABCG2, CD133 and uPAR rose in the mesothelioma lines. Bmi-1 rose markedly only in MSTO211H. OCT4A and OCT4B did not rise in any line, so OCT4 was dropped from the drug experiments.
  • In H28 cells, cisplatin significantly increased uPAR (p=0.002) and ABCG2 (p=0.02) and significantly reduced CD133 (p=0.04).
  • In H2052 cells, cisplatin produced no marked increase in the markers. In MSTO211H cells, cisplatin raised Bmi-1 (p=0.04), ABCG2 (p=0.03) and CD133 (p=0.001).
  • In normal MeT5A cells, cisplatin significantly reduced uPAR (p=0.0001) and ABCG2 (p=0.008), while CD133 was dramatically increased.
  • Pemetrexed significantly raised uPAR (p=0.001) and ABCG2 (p=0.0004) in H28 cells, raised CD133 (p=0.02) in H2052 cells, and significantly raised all markers in MSTO211H cells.
  • In normal MeT5A cells, pemetrexed reduced Bmi-1 (p=0.004) and ABCG2 (p=0.0002) and significantly raised CD133 (p=0.00003).
• The authors' conclusion: The authors concluded that their results suggest putative drug-resistant cancer stem cells exist in the three mesothelioma cell lines. They also concluded that the degree of resistance depends on the drug used and the mesothelioma subtype.

Topics

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

Medical terms in this study, explained in our Lexicon: STEM, Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta), Mesothelium, Chemotherapy, Mesothelial Cells.

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