Abstract 1920: Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas

Abstract

Abstract Background: Chronic inflammation is known to be a risk factor of carcinogenesis and tumor development, and it was demonstrated that oral aspirin intake reduced cancer-related death including pancreatic ductal adenocarcinoma (PDAC) through inhibiting prostaglandin synthases. On the other hand, cancer stem cells (CSCs) refer to a subset of tumor cells that have self-renewal ability and generate plenty of non-CSC cells that comprise a tumor. Prostaglandin E2 (PGE2) and inhibition of 15-PGDH, which is an enzyme degrading PGE2, promoted hematopoietic and tissue stem cell fraction, however, little is known about the role of PGE2 accumulation for CSC fraction. A number of CSC marker candidates have been explored to date, and Aldehyde dehydrogenase 1 (ALDH1) was identified as one of CSC markers in PDAC. The aim of this study is to elucidate the functional role of PGE2 in ALDH1 positive CSC fraction during tumor development in pancreas. Methods: The clonogenic growth potential of ALDH1-positive PDAC cells was assessed in vitro by growth assays and sphere formation assays. We next investigated the expression of ALDH1 and self-renewal related genes in PDAC cell lines with PGE2 or 15-PGDH inhibitor treatment. We further conducted functional experiments using siALDH1 in PDAC progression. Furthermore, we examined the effect of PGE2 for pancreatic tumorigenesis using Kras-driven genetic mouse model treated with 15-PGDH inhibitor. Finally, ALDH1 and Ki67 expression was examined by immunohistochemistry in 121 primary surgical specimens of PDAC and analyzed a relationship with clinicopathological factors and clinical outcomes. Results: The number of ALDH1-positive cells was significantly increased by PGE2 treatment, and PGE2 promoted growth and sphere formation potential in PDAC cells. In addition, 15-PGDH inhibitor induced PGE2 accumulation and gave rise to ALDH1-positive cells harboring high proliferating potential in PDAC cells. The growth and sphere formation potential were inhibited by silencing ALDH1 expression in PDAC cells. We next found that the expression of Nanog and Oct-4 genes was regulated by PGE2-ALDH1 signaling. Furthermore, 15-PGDH inhibitor induced ALDH1 expression and promoted PanIN formation in Kras-driven genetic mouse model. Finally, a high level of ALDH1 expression was significantly associated with large tumor size and high Ki67expression, and poor prognosis in PDAC patients. Conclusion: Current findings suggested that PGE2 positively regulated ALDH1 expression, and the growth and sphere formation potential were promoted by regulating self-renewal related genes expression, resulting in poor prognosis of PDAC patients. Inhibiting PGE2-ALDH1 signaling could lead to the suppression of tumor growth in PDAC patients. Citation Format: Kota Arima, Takatsugu Ishimoto, Masaki Ohmuraya, Keisuke Miyake, Tsugio Eto, Hirohisa Okabe, Yuki Kitano, Kensuke Yamamura, Takayoshi Kaida, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Hideo Baba. Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas [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 1920. doi:10.1158/1538-7445.AM2017-1920