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doi:10.1111/jgh.12660

GASTROENTEROLOGY

Clinical role of Notch signaling pathway in intraductal papillary mucinous neoplasm of the pancreas Tetsuya Ikemoto,1 Koji Sugimoto,1 Mitsuo Shimada, Tohru Utsunomiya, Yuji Morine, Satoru Imura, Yusuke Arakawa, Mami Kanamoto, Shu-ichi Iwahashi, Yu Saito and Shinichiro Yamada Department of Surgery, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan

Key words intraductal papillary mucinous neoplasms, Jagged1, Notch signaling, regulatory T cell. Accepted for publication 25 May 2014. Correspondence Tetsuya Ikemoto, Department of Digestive and Pediatric Surgery, Institute of Health Bioscience, Graduate School of Medicine, The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan. Email: [email protected] Declaration of conflict of interest The authors have no financial or other interests in entities related to the subject of this article. 1

These authors contributed equally to this study.

Abstract Background and Aim: This study was performed to elucidate the expression of the Notch signaling pathway and its correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs). It is incontrovertible that regulatory T cells (Tregs) play an important role in tumor immunity. However, the whole mechanism of control of peripheral Tregs remains unclear. It is also known that the Notch signaling pathway is involved in Treg suppressor function. Moreover, IPMNs have a high malignant potential. Methods: Peripheral blood samples and resected specimens from 18 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, and antiNotch2-intracellular domain antibody staining) and compared in terms of clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. Results: Disease-free survival was significantly worse in the Notch1 high-expression group (P = 0.023). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P = 0.012; Notch2-intracellular domain, P = 0.036). Jagged1 expression was significantly higher in IPMC than in IPMA (P < 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P < 0.01). Conclusions: Notch signaling, especially Jagged1 expression, reflects IPMN aggressiveness. Our data may suggest that the Notch signaling pathway is a key pathway that determines IPMN pathological aggressiveness and reflects the peripheral Treg population.

Introduction Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are characterized by their slow growth and highly malignant potential. However, the natural history of IPMNs is still controversial. In particular, the aggressiveness of branch-duct type IPMNs is difficult to assess preoperatively, as described in the established International IPMN/SCT Guidelines.1 Occasionally, IPMNs suddenly transform to invasive carcinomas during followup. Based on their individual resection experience, many researchers have reported that some clinicopathological factors, including cyst diameter, existence of nodules, or presence of tumor markers, are associated with IPMN aggressiveness; however, these findings are also controversial. Therefore, establishment of an accurate biomarker for IPMN aggressiveness is required. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases. Its overall survival is extremely low,

reportedly ranging from 0.4% to 5.0% in 5 years.2 Complete resection for radical cure of PDAC is important; however, there is no specific biomarker with which to screen PDAC and detect further metastasis. Thus, tumor immunity of patients with PDAC is examined with particular focus on regulatory T cells (Tregs). These cells were originally defined as a T-cell population with strong regulatory immunity against self-reactive T cells, and it was recently reported that Tregs play an important role in tumor environmental immunity.3–5 Indeed, the peripheral Treg population was shown to have a significant relationship to clinical staging of PDAC by careful retrospective immunomonitoring.6 However, the mechanism by which Tregs are expanded in the peripheral blood of patients with PDAC is still unclear. Therefore, we next considered that increasing peripheral Treg populations were responsible for dendritic cells (DCs) as professional antigen-presenting cells (APCs). Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolic enzyme that induces conversion of naïve CD4+ T-cells to

Journal of Gastroenterology and Hepatology 30 (2015) 217–222 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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Notch signaling pathway in IPMNs

(a) HE staining of each grade of IPMN

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(b) Notch1 staining

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IPMB (c) Disease-free survivals 100

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