Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma

Hiroki Sato,Harvey I Pass,Kazunori Tsukuda,Keisuke Aoe,Shinichi Toyooka,Shuta Tomida,Kazuhiko Shien,Hidejiro Torigoe,Hiroyuki Tao,Junichi Soh,Shinichiro Miyoshi,Kazunori Okabe,Kei Namba,Masakiyo Sakaguchi,Hiromasa Yamamoto,Takahiro Yoshioka

doi:10.1038/s41389-017-0017-3

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.

Highlights

Malignant pleural mesothelioma (MPM) is a highly invasive and aggressive tumor that develops in the mesothelial lining of the pleura
MPM cell lines were classified into three categories based on the secretion level of S100A11: High (YUMC44, H290, and H28), Low (HP-1, H2452, and H2052), and None (MSTO-211H)
These results suggest that S100A11 is aberrantly overexpressed in MPM at both cultured cells and clinical samples and secreted from MPM cells

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a highly invasive and aggressive tumor that develops in the mesothelial lining of the pleura. The median survival of patients with MPM from the time of diagnosis is usually less than 1 year[1,2]. Most MPM cases are of advanced-stage disease, for which. Proteins of the S100 family are small molecules (ranging from 9 to 14 kDa) with two EF-hands and in humans, the family is composed of 20 different members (S100A1–S100A16, S100β, S100G, S100P, and S100Z). This group of proteins modulates a variety of cellular processes, including cell proliferation, differentiation, and intracellular signaling by functioning both as intracellular Ca2+ sensors and as extracellular factors[3,4,5]. We previously reported that S100A11 has two ambivalent functions in the cells

Methods

Results

Conclusion