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In intraductal papillary mucinous neoplasms (IPMNs), the presence of a mural nodule showing a papillary or nodular proliferation of tumor cells in the dilated pancreatic duct is an indication for resection of IPMN. Solute carrier family 2, facilitated glucose transporter member 1, known as glucose transporter type 1 (SLC2A1/GLUT1) mediates cellular glucose uptake in many carcinomas and is correlated with increased 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake. We examined SLC2A1/GLUT1 expression in the mural nodules of 180 IPMN specimens to distinguish malignant/benign tumors. A mural nodule was detected in 80 (44.4%) of the IPMNs, and was detected in 18.6% (13/70) of the IPMN-low (dysplasia) specimens, 36.1% (13/36) of the IPMN-int, 93.3% (28/30) of the IPMN-high, and 59.1% (26/44) of the IPMN-inv (with an associated invasive carcinoma) specimens. The sensitivity for detecting mural nodules was 81.7% by endoscopic ultrasonography, 70% by contrast-enhanced computed tomography and 54% by endoscopic retrograde cholangiopancreatography. SLC2A1/GLUT1 expression in the mural nodules was recognized in the basal and basolateral cytomembrane of tumor cells and was expressed in 15.4% (2/13) of the IPMN-low, 15.4% (2/13) of the IPMN-int, 71.4% (20/28) of the IPMN-high and 84.6% (22/26) of the IPMN-inv groups. The SLC2A1/GLUT1 expression was significantly higher in the IPMN-high and IPMN-inv mural nodules than in those of the IPMN-low and IPMN-int groups. Our findings suggest that SLC2A1/GLUT1 is expressed late in the adenoma-carcinoma sequence during carcinogenesis in IPMN, and SLC2A1/GLUT1 act as therapeutic target for malignant IPMN., (Copyright © 2017. Published by Elsevier Inc.)

Glucose transporter (GLUT)-1 is expressed in malignant tumors and correlated with poor outcome in several cancers. Biliary intraepithelial neoplasia (BilIN) is considered to be a precursor or a noninvasive lesion of invasive cholangiocarcinoma. We examined GLUT-1 and GLUT-2 expression in 149 intrahepatic cholangiocarcinomas and 39 BilINs immunohistochemically and evaluated their correlation with clinicopathological findings and patient outcome in intrahepatic cholangiocarcinoma. Furthermore, we examined the role of GLUT-1 on migration and invasion of cholangiocarcinoma cells using GLUT-1 siRNA. In intrahepatic cholangiocarcinoma, GLUT-1 expression was frequently observed near the necrotic areas, whereas GLUT-2 expression tended to be observed in adenocarcinoma of large bile ducts. Compared with the GLUT-1-negative group, the GLUT-1-positive group showed significantly larger tumor size (P = .0031), poor differentiation (P < .0001), frequent lymphatic invasion (P = .0031) and lymph node metastasis (P < .0001), and high HIF-1α expression (P = .0297). GLUT-2 expression was significantly correlated with good differentiation (P = .0015), perihilar location (P < .0001), perineural invasion (P = .0049), and lymph node metastasis (P = .0248). The patients with GLUT-1-positive tumors showed poor disease related survival (P < .0001). The numbers of migrating and invading cells were significantly decreased in GLUT-1 siRNA transfectants of cholangiocarcinoma cells. Although, GLUT-1 was expressed in all grades of BilINs, GLUT-2 was expressed only in high-grade BilINs. Our results suggest that GLUT-1 expression correlates aggressive behavior and poor prognosis, and that GLUT-1 might be a therapeutic target of cholangiocarcinoma. GLUT-2 expression may be associated with cholangiocarcinogenesis of large bile duct and is a helpful marker for detecting high-grade BilIN lesions in atypical bile ducts., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanINs) are important premalignant lesions of pancreatic cancer. Ezrin is a member of the ezrin, radixin, and moesin protein family and acts as a cross-linker between the plasma membrane and the actin cytoskeleton. We investigated the roles of ezrin during carcinogenesis in IPMN and invasive ductal carcinoma and examined whether ezrin was a prognostic factor. We examined ezrin and phosphorylated ezrin (p-ezrin) expression in 131 IPMNs, 47 PanINs, and 59 invasive ductal carcinomas by immunohistochemical staining. Ezrin and p-ezrin (tyr354) expressions were significantly higher in IPMN with an associated invasive carcinoma, compared with those in IPMN with high-grade dysplasia (P = .03 and P = .0007, respectively). In all grades of PanINs, ezrin and p-ezrin (tyr353) were highly expressed. In patients with invasive ductal carcinoma, the presence of PanIN-2 or PanIN-3 was significantly correlated with positive ezrin and p-ezrin (tyr353) expression of the invasive ductal carcinoma component (P = .01 and P = .0004). The negative p-ezrin (tyr353) expression group of invasive ductal carcinoma showed a significantly worse prognosis than did the positive p-ezrin (tyr353) expression group by survival analysis (P = .04) and was a statistically significant adverse prognostic factor by both univariate and multivariate analyses (P = .048 and P = .015). Ezrin phosphorylation sites differ between the developments of IPMN and PanIN. Although p-ezrin (tyr354) expression in IPMNs is associated with tumor invasion, p-ezrin (tyr353) expression in invasive ductal carcinoma plays an important role not in tumor invasion and metastasis but in the early development of PanINs., (Copyright © 2013 Elsevier Inc. All rights reserved.)