Background: 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. In addition, CSCs play crucial roles in various processes during tumor progression and metastasis as well. A number of CSC markers candidates have been explored to date, and Aldehyde dehydrogenase 1 (ALDH1), c-Met, and CD44 have been identified as CSC markers in pancreatic ductal adenocarcinoma (PDAC). On the other hand, prostaglandin E2 (PGE2) is one of metabolites in arachidonate cascade and is implicated in the expansion of hematopoietic and tissue stem cell fraction. The aim of this study is to single out the most important CSC marker and elucidate the functional role of PGE2 for CSC expansion in PDAC.
Methods: Three CSC markers (ALDH1, CD44, and c-Met) expression was examined by immunohistochemistry in 121 primary surgical specimens of PDAC and analyzed a relationship with clinicopathological factors and clinical outcomes. The clonogenic growth potential of CSC marker-positive PDAC cells was assessed in vitro by growth assays and sphere formation assays. We next investigated the expression of CSC markers and self-renewal related genes in PDAC cell lines with PGE2 or 15-PGDH inhibitor treatment. We further conducted functional experiments using siRNA to identify the critical molecule in PDAC progression.
Results: A high level of ALDH1 expression was detected in 63 of the 121 cases, and was significantly associated with large tumor size and poor prognosis in PDAC patiants. On the other hand, CD44 and c-Met expression were not associated with the prognosis. Among CSC markers, the expression of ALDH1 was significantly increased by PGE2 treatment in PDAC cells. By suppressing ALDH1 expression by siRNA, growth and sphere formation potential were inhibited in ALDH1 high-expressing PDAC cells. In contrast, the expression of ALDH1 was remarkably increased by PGE2 or 15-PGDH inhibitor treatment in ALDH1 low-expressing PDAC cells. Finally, we found that Nanog and Oct-4 were down-stream molecules of PGE2-ALDH1 signaling and played crucial roles for PDAC cell expansion.
Conclusion: Our results demonstrated that PGE2 positively regulated ALDH1 expression, and the growth and sphere formation potential were promoted by increasing ALDH1 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, Hirohisa Okabe, Yuki Kitano, Risa Inoue, Kensuke Yamamura, Takayoshi Kaida, Takaaki Higashi, Katsunobu Taki, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Toru Beppu, Hideo Baba. Verification of mechanism that CSC markers are implicated in poor prognosis for pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3350.