Clinical role of <scp>N</scp>otch signaling pathway in intraductal papillary mucinous neoplasm of the pancreas

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background and Aim</jats:title><jats:p>This study was performed to elucidate the expression of the Notch signaling pathway and its correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (<jats:styled-content style="fixed-case">IPMN</jats:styled-content>s). It is incontrovertible that regulatory <jats:styled-content style="fixed-case">T</jats:styled-content> cells (<jats:styled-content style="fixed-case">T</jats:styled-content>regs) play an important role in tumor immunity. However, the whole mechanism of control of peripheral <jats:styled-content style="fixed-case">T</jats:styled-content>regs remains unclear. It is also known that the <jats:styled-content style="fixed-case">N</jats:styled-content>otch signaling pathway is involved in <jats:styled-content style="fixed-case">T</jats:styled-content>reg suppressor function. Moreover, <jats:styled-content style="fixed-case">IPMN</jats:styled-content>s have a high malignant potential.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Peripheral blood samples and resected specimens from 18 patients with <jats:styled-content style="fixed-case">IPMN</jats:styled-content> were evaluated. All patients were pathologically diagnosed with <jats:styled-content style="fixed-case">IPMN</jats:styled-content>. Resected specimens were immunohistochemically evaluated (anti‐<jats:styled-content style="fixed-case">N</jats:styled-content>otch1, anti‐<jats:styled-content style="fixed-case">N</jats:styled-content>otch2, and anti‐<jats:styled-content style="fixed-case">N</jats:styled-content>otch2‐intracellular domain antibody staining) and compared in terms of clinicopathological factors. Peripheral <jats:styled-content style="fixed-case">T</jats:styled-content>reg populations were analyzed with an automated flow cytometer.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Disease‐free survival was significantly worse in the <jats:styled-content style="fixed-case">N</jats:styled-content>otch1 high‐expression group (<jats:italic>P</jats:italic> = 0.023). <jats:styled-content style="fixed-case">N</jats:styled-content>otch2 family expressions were higher in intraductal papillary mucinous carcinoma (<jats:styled-content style="fixed-case">IPMC</jats:styled-content>) than in intraductal papillary mucinous adenoma (<jats:styled-content style="fixed-case">IPMA</jats:styled-content>) (<jats:styled-content style="fixed-case">N</jats:styled-content>otch2, <jats:italic>P</jats:italic> = 0.012; <jats:styled-content style="fixed-case">N</jats:styled-content>otch2‐intracellular domain, <jats:italic>P</jats:italic> = 0.036). <jats:styled-content style="fixed-case">J</jats:styled-content>agged1 expression was significantly higher in <jats:styled-content style="fixed-case">IPMC</jats:styled-content> than in <jats:styled-content style="fixed-case">IPMA</jats:styled-content> (<jats:italic>P</jats:italic> < 0.05) and was significantly related to recurrence. The <jats:styled-content style="fixed-case">T</jats:styled-content>reg population in peripheral blood was higher in patients with <jats:styled-content style="fixed-case">IPMC</jats:styled-content> than in those with <jats:styled-content style="fixed-case">IPMA</jats:styled-content> (<jats:italic>P</jats:italic> < 0.01).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p><jats:styled-content style="fixed-case">N</jats:styled-content>otch signaling, especially <jats:styled-content style="fixed-case">J</jats:styled-content>agged1 expression, reflects <jats:styled-content style="fixed-case">IPMN</jats:styled-content> aggressiveness. Our data may suggest that the <jats:styled-content style="fixed-case">N</jats:styled-content>otch signaling pathway is a key pathway that determines <jats:styled-content style="fixed-case">IPMN</jats:styled-content> pathological aggressiveness and reflects the peripheral <jats:styled-content style="fixed-case">T</jats:styled-content>reg population.</jats:p></jats:sec>