Significance of osteopontin in the sensitivity of malignant pleural mesothelioma to pemetrexed

Our plain-English summary of Significance of osteopontin in the sensitivity of malignant pleural mesothelioma to pemetrexed, by S. Takeuchi, M. Seike, R. Noro, et al (International Journal of Oncology, 2014).

The study

• Authors: S. Takeuchi, M. Seike, R. Noro, C. Soeno, T. Sugano, F. Zou, H. Uesaka, N. Nishijima, M. Matsumoto, Y. Minegishi, K. Kubota, A. Gemma
• Journal: International Journal of Oncology
• Published: 2014;44(6):1886-94
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed (PEM) is currently recommended as one of the standard anticancer drugs for malignant pleural mesothelioma (MPM). However, the mechanism of the sensitivity of MPM to PEM remains unclear. We analyzed the antitumor effects of PEM in six MPM cell lines by MTS assay. To identify genes associated with drug sensitivity, we conducted gene expression profiling on the same set of cell lines using GeneChips and pathway analysis. Three cell lines were sensitive to PEM. A total fo 18 transcripts and 14 genes identified by GeneChips were significantly correlated with sensitivity to PEM. Pathway analysis revealed that osteopontin (SPP1/OPN) was an important target in PEM sensitivity. Overexpression of SPP1/OPN was observed in the sensitive cells by quantitative PCR and western blot analysis. Introduction of SPP1/OPN by lentiviral vector significantly enhanced the invasion activities of MPM cells. PEM treatment with SPP1/OPN knockdown inhibited the PEM-induced cell growth-inhibitory effect in PEM-sensitive cells. Expression of SPP1/OPN and AKT phosphorylation significantly decreased after PEM treatment of the PEM-sensitive cells. High immunohistochemical expression of SPP1/OPN was observed in two of three MPM patients who had a partial response to PEM-based chemotherapy. PEM has antitumor effects in MPM cells dependent on SPP1/OPN overexpression resulting in AKT activation. Our results suggest that SPP1 may be used as a single predictive biomarker of the effectiveness of PEM treatment in MPM.

In plain English

This laboratory study looked at why some malignant pleural mesothelioma cells respond to the cancer drug pemetrexed. The authors tested pemetrexed on six mesothelioma cell lines grown in the laboratory. They classed three (H28, 211H and H2052) as sensitive and three (H2452, MESO1 and MESO4) as resistant. Gene activity profiling found 18 transcripts and 14 genes linked to sensitivity, and further analysis pointed to a protein called osteopontin (SPP1/OPN). Osteopontin gene levels were significantly higher in the sensitive cell lines. When the authors suppressed osteopontin in the sensitive cells, pemetrexed's growth-blocking effect was reduced. Adding osteopontin to resistant cells increased their invasive activity but did not change their drug sensitivity. The authors also examined tumor samples from six patients treated with pemetrexed plus a platinum drug. Two of the three who had a partial response stained positive for osteopontin, and none of the three with stable disease did. The authors concluded that osteopontin may be usable as a predictive marker of pemetrexed's effectiveness, and noted that the number of patient samples was very small. Asbestos exposure was not studied.

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) study of mesothelioma cell lines, with immunohistochemical staining of tumor specimens from a small number of treated patients
• Who was studied: Six malignant pleural mesothelioma cell lines (NCI-H28, NCI-H2452 and ACC-MESO4 epithelial type; NCI-H2052 sarcomatoid type; ACC-MESO1 fibrous; MSTO-211H biphasic), plus tumor specimens from 6 patients treated with pemetrexed and a platinum agent from 2007 to 2011 at Nippon Medical School Hospital, Japan
• Exposure: The cancer drug pemetrexed (PEM). Cisplatin and gemcitabine were also tested on the cell lines. Patients received pemetrexed with cisplatin or carboplatin. Asbestos exposure was not studied.
• Main results:
  • Three of six cell lines were sensitive to pemetrexed: H28 and 211H were highly sensitive (IC50 below 0.1 µM) and H2052 was intermediate-sensitive. H2452, MESO1 and MESO4 were resistant.
  • Gene expression profiling of the six cell lines found 18 transcripts and 14 genes significantly correlated with pemetrexed sensitivity.
  • Osteopontin (SPP1/OPN) gene expression was significantly higher in the pemetrexed-sensitive cell lines than in the resistant ones.
  • In 2 of the 3 sensitive cell lines, treatment with 1 µM pemetrexed significantly reduced osteopontin levels.
  • Introducing osteopontin into resistant H2452 and MESO1 cells significantly enhanced their invasion activity.
  • Suppressing osteopontin with siRNA in the three sensitive cell lines diminished pemetrexed's growth-inhibitory effect. IC50 values with suppression were 0.48, more than 100 and more than 100 µM for H28, 211H and H2052, compared with 0.007, 0.01 and 9.3 µM without suppression.
  • Adding osteopontin to the resistant H2452 and MESO1 cells did not change their sensitivity to pemetrexed (data not shown in the article).
  • Phosphorylated AKT significantly decreased after pemetrexed treatment of sensitive H28 cells, but did not change in resistant MESO1 cells.
  • In patient specimens, 2 of the 3 patients with a partial response to chemotherapy were positive for osteopontin, and none of the 3 with stable disease showed positive staining.
• The authors' conclusion: The authors concluded that pemetrexed has antitumor effects in mesothelioma cells that depend on osteopontin overexpression leading to AKT activation, and that osteopontin may be used as a single predictive biomarker of how well pemetrexed works in malignant pleural mesothelioma.
• Limitations the authors state:
  • The number of patient samples was very small.

Topics

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

Medical terms in this study, explained in our Lexicon: Osteopontin, Pleural Mesothelioma, Pemetrexed (Alimta), Chemotherapy, Biomarker.

Related studies

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• Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed — L. Cortes-Dericks, G.L. Carboni, et al. (2010)
• Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma — O.D. Røe, A. Szulkin, et al. (2012)
• Pharmacokinetic evaluation of pemetrexed — J.B. Sørensen (2011)
• Pemetrexed in the treatment of malignant mesothelioma: results from an expanded access program in Germany — M. Reck, R.A. Stahel, et al. (2010)
• Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells — L. Su, G. Liu, et al. (2011)

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