Abstract 30: S100A11 is a prominent therapeutic target in malignant pleural mesothelioma

Abstract

Abstract [Background & Purpose] Malignant pleural mesothelioma (MPM) is an aggressive tumor arising from the mesothelial cells that show a serious malignancy in thoracic cavity with a median survival time of 9-12 months. The therapeutic approaches in clinical standard are limited to surgery and chemotherapy for early and advanced stages, respectively. The strategies unfortunately provide only palliation, thus further advanced approach is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancer tissues. It has been reported that S100A11 plays an important role in progression of many cancers derived from thyroid, ovarian and lung tissues, but its roles and signature in MPM are poorly understood. In this study, we investigated the impact of S100A11 in MPM cell lines and resected tumors. [Material & Methods] We explored the expression of S100A11 in 7 MPM cell lines (HP-1, H28, MSTO-211H, H2052, H290, H2452, and YUMC44) and 2 normal mesothelial cell lines (Met-5A and LP-9). We analyzed the effect of S100A11 on cell proliferation, colony formation, migration, invasion and downstream signaling. The efficacy of anti-S100A11 antibody on cell proliferation and downstream signaling was also determined. [Results] We found that S100A11 protein was consistently upregulated in 7 MPM cell lines at a significant level in comparison to 2 normal mesothelial cells. The same phenomenon was also confirmed in MPM tissue sections by immunohistochemistry, i.e., S100A11 was strongly stained at MPM cells, but not at surrounding normal lung cells. Specific knockdown of S100A11 by small interfering RNA turned the aggressive cells into the attenuated phenotypes for proliferation, invasion and migration. Those were notably observed in both 2 MPM cell lines (H2052 and H2452). Interestingly, we found that MPM cell lines but not normal cells actively secreted the S100A11 protein. To pursue this, we next tried to inhibit the function of the secreted S100A11. Administration of S100A11 neutralizing antibody significantly inhibited the proliferation of 4 MPM cell lines (H2052, H2452, H28, and H290). The antibody had no effect on the proliferation of only one MPM cell line, MSTO-211H, which showed no secretion of S100A11. Taken together, these results suggest that S100A11 secreted from MPM cells can be a prominent target for effective MPM therapy. [Conclusion] Our results suggest that S100A11 is a possible therapeutic target in MPM. Citation Format: Hiroki Sato, Hiromasa Yamamoto, Kei Namba, Hidejiro Torigoe, Takahiro Yoshioka, Kazuhiko Shien, Junichi Soh, Shinichi Toyooka. S100A11 is a prominent therapeutic target in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 30. doi:10.1158/1538-7445.AM2017-30