Elsevier

Human Pathology

Volume 45, Issue 8, August 2014, Pages 1610-1617
Human Pathology

Original contribution
Different expression of glucose transporters in the progression of intrahepatic cholangiocarcinoma,☆☆

https://doi.org/10.1016/j.humpath.2014.03.008Get rights and content

Summary

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.

Introduction

Malignant cells require a steady source of energy to maintain growth and proliferation. Cancer cells preferentially use glycolysis for their energy supply, even in aerobic conditions [1]. Glucose uptake is mediated by glucose transporters (GLUTs), and GLUT-1 expression is increased in various cancers [2], [3], [4], [5]. Furthermore, a close relationship between high GLUT-1 expression and poor outcomes has been described in several cancers [2], [6], [7], [8], [9].

Tissue hypoxia contributes to the progression of many human cancers by inducing the up-regulation of genes associated with angiogenesis, cell survival, cell proliferation, apoptosis, and metabolism [10]. This activation is accomplished by hypoxia-inducible factors (HIFs), which accumulate in tissues under the hypoxic conditions often present in growing tumors. GLUT-1 is a downstream target gene of HIF-1α [10], [11].

Cholangiocarcinoma is the second most common type of primary liver cancer. In a previous study, GLUT-1 was a major glucose transporter in cholangiocarcinoma and was highly expressed in moderately to poorly differentiated types than in well differentiated types [12]. However, a detailed and large-scale analysis of the GLUT proteins in cholangiocarcinoma samples has never been reported. The first aim of this study was to assess whether GLUT-1 and GLUT-2 protein expression was associated with clinicopathologic and biological variables, and with outcomes.

Biliary intraepithelial neoplasia (BilIN) is considered a precursor or noninvasive lesion of invasive cholangiocarcinoma of the hilar or perihilar region. It is often difficult to diagnose BilIN lesions morphologically, and it is necessary to establish a sensitive diagnostic method. The second aim of this study was to investigate GLUT-1 and GLUT-2 expression in precursor lesions of cholangiocarcinoma.

GLUT-1 expression was correlated with higher malignant potential in several cancers. Then, the role of GLUT-1 expression in migration and invasion was examined by using GLUT-1 siRNA in cholangiocarcinoma cell lines.

Section snippets

Tissue samples

Tumors and biliary lesions of the current study were surgically resected and diagnosed at the Department of Anatomic Pathology of Kyushu University from 1985 to 2008. Our study protocol was accepted by the institutional review board of Kyushu University (25-121) and conformed to the ethics guidelines of the 1975 Declaration of Helsinki. For strict privacy protection, identifying information for all samples was removed before analysis. One hundred forty-nine cases of available paraffin-embedded

Comparison of GLUT-1 and GLUT-2 expression and clinicopathological findings

In intrahepatic cholangiocarcinoma, GLUT-1 membranous expression was frequently observed near the necrotic areas (Fig. 1A), and GLUT-2 membranous and/or cytoplasmic expression was detected in the adenocarcinoma of perihilar location (Fig. 1B), in particular, non-invasive lesions. Red blood cells were strongly positive for GLUT-1, and hepatocytes were positive for GLUT-2. The percentage of the GLUT-1 positive group was 46% (69/149), and that of the GLUT-2 positive group was 21% (31/149).

Discussion

GLUT-1 expression correlates with poor outcome in several digestive cancers, such as hepatocellular carcinoma [14], pancreatic carcinoma [15], gallbladder cancer [16], esophageal cancer [17], gastric cancer [18], colon cancer [19], and rectal cancer [20]. A previous study showed that GLUT-1 is expressed especially in moderately to poorly differentiated cholangiocarcinoma [12]. However, no study has evaluated the relationship between GLUT-1 expression and outcomes in cholangiocarcinoma. In the

Acknowledgments

The authors appreciate the technical support from Ms. Tateishi and the Research Support Center, Graduate School of Medical Sciences, Kyushu University. English usage in this paper was reviewed by KN International.

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    Disclosure/Conflict of Interest: The authors declare no conflict of interest.

    ☆☆

    Funding disclosure: This study is supported by Grant-in-Aid for Scientific Research (C) (No.23590399) from the Japan Society for the Promotion of Science.

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