Abstract 1406: High expression of DPD and ALDH1 are associated with poor prognosis in pancreatic cancer
Authors: Arima Kota , Okabe Hirohisa , Hashimoto Daisuke , Kaida Takayoshi , Higashi Takaaki , Taki Katsunobu , Takeyama Hideaki , Nitta Hidetoshi , Hayashi Hiromitsu , Chikamoto Akira , Beppu Toru , Baba Hideo 
Published: August 2015

Abstract
Background: Pancreatic cancer is a highly aggressive disease and currently the fourth leading cause for cancer related mortality. The annual incidence of it has been shown to be approximately equal to the annual death rate caused by it because of the propensity for early metastatic spread and because the disease is highly resistant to radiation and chemotherapy. Recently, cancer stem cells may play a crucial role in the development and progression of tumor. According to recent studies, cancer stem cell population in human pancreatic cancers are expressing the cell surface markers CD44+, c-Met, and ALDH1. 5-Fluorouracil (5-FU) is one of the key drugs and widely used in the treatment of pancreatic cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for 5-FU catabolism in liver, and it was reported that high DPD expression in cancer tissue was associated with 5-FU resistance and poor prognosis. The aim of this study is to examine if the pancreatic cancer stem cells express high DPD as a result acquiring chemoresistance to 5-FU.
Methods: A total of 121 patients who underwent curative pancreatectomy for pancreatic cancer from April 2002 to December 2013 were analyzed. Immunohistochemical staining of DPD, ALDH1 and c-Met was performed using paraffin-embedded section of tissues. Expression of them were analyzed in interrelationship each other. Clinical relevance of those markers was confirmed with clinicopathological characteristics that were prospectively collected in our database.
Results: Immunohistochemical analysis on clinical sample revealed that DPD expression was high in 55 (45.5%) patients, and high c-Met and ALDH1 expression were seen in 58 (47.9%) and 58 (47.9%) patients retrospectively. ALDH1 activity, DPD expression and sensitivity to 5-FU were examined using pancreatic cancer cell lines in vitro. High DPD expression was significantly associated with high ALDH1 expression not but c-Met, and associated with elderly patients (P = 0.0294) and overall survival (P = 0.0274). Pancreatic cell line with high DPD expression was more resistant to 5-FU than cells with low DPD expression in vitro. Low c-Met expression was significantly associated with high local infiltration (P = 0.0102). ALDH1 expression was significantly associated with relapse free survival (P = 0.0392) and overall survival (P = 0.0358).
Conclusion: Our study demonstrated that high DPD expression was significantly associated with specific pancreatic cancer stem cell marker expression, may be involved in resistance to 5-FU treatment in pancreatic cancer.
Citation Format: Kota Arima, Hirohisa Okabe, Daisuke Hashimoto, Takayoshi Kaida, Takaaki Higashi, Katsunobu Taki, Hideaki Takeyama, Hidetoshi Nitta, Hiromitsu Hayashi, Akira Chikamoto, Toru Beppu, Hideo Baba. High expression of DPD and ALDH1 are associated with poor prognosis in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1406. doi:10.1158/1538-7445.AM2015-1406