Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma

Our plain-English summary of Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma, by H. Sato, M. Sakaguchi, H. Yamamoto, et al (Oncogenesis, 2018).

The study

• Authors: H. Sato, M. Sakaguchi, H. Yamamoto, S. Tomida, K. Aoe, K. Shien, T. Yoshioka, K. Namba, H. Torigoe, J. Soh, K. Tsukuda, H. Tao, K. Okabe, S. Miyoshi, H.I. Pass, S. Toyooka
• Journal: Oncogenesis
• Published: 2018;7(1):11
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

In plain English

This laboratory study examined a protein called S100A11 in malignant pleural mesothelioma (MPM). It did not measure asbestos exposure. Six of seven MPM cell lines released S100A11 into the surrounding fluid, while two normal mesothelial cell lines released none. An antibody that blocks S100A11 slowed the growth of MPM cell lines that released it, although lines releasing more needed a higher dose. The antibody also reduced migration and invasion of MPM cells. It did not change the growth of the one MPM line that released none. In mice with implanted MPM tumors (three mice, six tumors per group), antibody-treated tumors grew significantly less than control tumors. In pleural fluid from 29 MPM patients, 11 benign asbestosis patients and 12 post-surgery patients, S100A11 was significantly higher in MPM fluid than in benign asbestosis fluid (P = 0.014) or post-surgery fluid (P less than 0.001). It was also higher in benign asbestosis fluid than in post-surgery fluid (P = 0.041). The authors concluded that extracellular S100A11 may be a therapeutic target in S100A11-secreting MPM, and they suggested it could be a diagnostic marker.

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 study: experiments on cultured cell lines, a mouse xenograft (implanted tumor) experiment, and measurement of S100A11 in patients' pleural fluid samples
• Who was studied: Seven human MPM cell lines, 2 normal mesothelial cell lines and other cancer cell lines. Female NOD/SCID mice, 3 per group with two tumors per mouse. Pleural fluid from 29 MPM patients (10 biphasic, 15 epithelioid, 4 sarcomatoid), 11 benign asbestosis (BA) patients and 12 patients after thoracic surgery (10 lung cancer, 2 pulmonary cyst), at Okayama University Hospital and the National Hospital Organization Yamaguchi-Ube Medical Center, Japan
• Exposure: Not an asbestos exposure study. The treatment tested was an anti-S100A11 neutralizing antibody (100 ng/ml or 1 μg/ml in cell cultures; 1 µg/ml injected with tumor cells in mice), compared with control mouse IgG. Benign asbestosis patients served as one comparison group for pleural fluid levels.
• Main results:
  • Six of seven MPM cell lines secreted S100A11 (all except MSTO-211H); the normal mesothelial cell lines secreted none
  • In "Low"-secreting MPM cell lines (H2452 and H2052), the antibody at 100 ng/ml strongly suppressed growth
  • In "High"-secreting MPM cell lines (H290 and H28), 100 ng/ml had no appreciable effect, but 1 μg/ml suppressed growth
  • In the non-secreting MPM cell line MSTO-211H, the antibody did not affect growth at any dose
  • Antibody-treated MPM cells showed significantly reduced migration and invasion
  • In mice, antibody treatment significantly reduced growth of H2452 and H290 tumors compared with control IgG (six tumors per group)
  • S100A11 in pleural fluid was higher in MPM patients than in benign asbestosis patients (P = 0.014)
  • S100A11 in pleural fluid was higher in MPM patients than in postoperative patients (P less than 0.001)
  • S100A11 in pleural fluid was higher in benign asbestosis patients than in postoperative patients (P = 0.041)
• The authors' conclusion: The authors concluded that extracellular S100A11 can be a therapeutic target in S100A11-secreting MPM, because normal cells did not secrete it. They also suggested it could serve as an early diagnosis marker.
• Limitations the authors state:
  • The mouse experiment had no randomization and no blinding, and its sample size was based on the authors' previous experience
  • Blocking the receptor RAGE (with sRAGE) had a limited growth-inhibiting effect compared with the antibody, suggesting that another receptor may be involved
  • The possible adverse effects of inhibiting RAGE signaling are still unclear

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Chemotherapy, Mesothelial Cells, Pleural Effusion, Biomarker.

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• DNA copy number gains in malignant pleural mesothelioma — M. Furukawa, S. Toyooka, et al. (2015)
• The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma — T. Muraoka, J. Soh, et al. (2013)
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• Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors — X.Y. Zhao, B. Subramanyam, et al. (2016)

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