Impact of Snail and E-cadherin expression in pancreatic neuroendocrine tumors

Abstract

Abstract. Pancreatic neuroendocrine tumors (PNETs) are a rare type of malignancy with a prognosis that is relatively good, compared with that of pancreatic adenocarcinoma. However, a number of patients with PNETs have distant metastasis and a less favorable prognosis. Epithelial-mesenchymal transition (EMT) is essential for tumor progression and metastasis. Snail and E-cadherin serve key roles in the process of EMT in numerous tumor types, including gastric and pancreatic adenocarcinoma. However, the role of EMT in PNETs remains unclear. The aim of the present study was to investigate the significance of Snail and E-cadherin expression in PNETs. Tissue samples were obtained from 40 resected PNETs. The expression of Snail and E-cadherin was evaluated in the primary tumors using immunohistochemical staining. The association between protein expression and patient clinicopathological features was then analyzed. High and low Snail expression levels were observed in 11 (27.5%) and 29 (72.5%) patients, respectively. Preserved and reduced E-cadherin expression was observed in 19 (47.5%) and 21 (52.5%) patients, respectively. Patients with low Snail expression and preserved E-cadherin expression had a significantly lower risk of vascular invasion, lymphatic invasion, lymph node metastasis and liver metastasis and a lower WHO classification, as compared with the group that included patients with high Snail and reduced E-cadherin, high Snail and preserved E-cadherin, and low Snail and reduced E-cadherin expression. In addition, the patients with low Snail expression levels and preserved E-cadherin expression had more a favorable prognosis compared with the other group. The present study indicates that EMT serves an important role in tumor progression in PNETs. Immunohistochemical evaluation of Snail and E-cadherin is useful for predicting the risk of vessel invasion and metastasis in PNETs. IntroductionPancreatic neuroendocrine tumors (PNETs) are a rare type of malignancy with an annual incidence of 1/100,000 people, and account for ~1-2% of all pancreatic tumors (1). PNETs are divided into functional tumors, which cause specific hormonal syndromes such as hypoglycemic attack, and non-functional tumors (2). The prognosis of PNETs is relatively favorable compared with that for pancreatic adenocarcinoma; however, certain patients with PNETs exhibit distant metastasis and have a less favorable prognosis (3). In 2010, the World Health Organization (WHO) categorized PNETs into G1 and G2 PNETs and neuroendocrine carcinoma (NEC), based on mitotic counts and the Ki-67 index (4). These classifications are useful for predicting prognosis and postoperative recurrence (5,6). However, certain patients with low-risk pathologic features may unexpectedly experience distant metastasis and postsurgical recurrence (5). Little is currently known about the underlying molecular mechanisms by which distant metastasis is promoted in patients with PNETs.Invasion into the surrounding normal tissue is a critical step for primary tumors to metastasiz...

Arachidonic acid-induced Ca2+ entry and migration in a neuroendocrine cancer cell line

“…The findings were consistent with NMT phenotype. Of note, the E-cadherin signal in BON cells had an atypical nuclear distribution, similar to that previously shown to correlate with invasiveness in pancreatic NETs [ 34 ].…”

“…In BON cells that express both epithelial and neuroendocrine features, this can be achieved via neuroendocrine-to-mesenchymal transition (NMT). This transition is characterized by a reduction in neuroendocrine markers and altered expression of mesenchymal proteins [ 32 – 34 ]. Thus, we assessed whether AA treatment could induce morphological changes and alter expression of markers of NMT including chromogranin A (CGA) E-cadherin, α-smooth muscle actin (α-SMA) and snail family transcriptional repressor 1 (Snail1).…”

Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice

“…Similarly to other cancers, NET cells may acquire invasive potential through the epithelial-to-mesenchymal transition (EMT), a transdifferentiation program conferring mesenchymal plasticity to epithelial cells [20]. Multiple studies have demonstrated that the EMT drives the progression of both well- and poorly differentiated NETs, and that EMT-undergone tumors have a dismal prognosis, as demonstrated by the association between poor outcomes and the overexpression of EMT-related factors including snail, slug, twist and vimentin in tumor cells [21-27]. In this context, bone-colonizing NETs have been shown to harbor specific EMT-related features.…”

High vimentin expression with E-cadherin expression loss predicts a poor prognosis after resection of grade 1 and 2 pancreatic neuroendocrine tumors

“…To date, a few studies have been conducted to evaluate the expression of EMT-specific transcription factors in neuroendocrine tumors [ 26 – 28 ]. Fendrich et al immunohistochemically evaluated the expression of the EMT factors Snail, Twist and E-cadherin in human pNETs and showed overexpression of Snail and Twist and loss of E-cadherin expression in the majority of malignant pNETs [ 26 ], which was similar to the results of Yonemori K [ 29 ]. However, no statistically significant correlation was found between Snail/Twist expression or loss of E-cadherin expression and OS, but there was an inverse association between E-cadherin and Snail/Twist.…”