Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer

胆管がんにおけるL型アミノ酸トランスポーター1発現の予後因子としての臨床的な重要性と新規標的治療の可能性

解良 恭一*; 須納瀬 豊*; 大島 康宏; 石岡 典子; 荒川 和久*; 小川 哲史*; 砂長 則明*; 清水 公裕*; 富永 英之*; 織内 昇*; 伊藤 秀明*; 永森 收志*; 金井 好克*; 山口 藍子*; 瀬川 篤記*; 井出 宗則*; 森 昌朋*; 小山 徹也*; 竹吉 泉*

Kaira, Kyoichi*; Sunose, Yutaka*; Ohshima, Yasuhiro; Ishioka, Noriko; Arakawa, Kazuhisa*; Ogawa, Tetsushi*; Sunaga, Noriaki*; Shimizu, Kimihiro*; Tominaga, Hideyuki*; Oriuchi, Noboru*; Ito, Hideaki*; Nagamori, Shushi*; Kanai, Yoshikatsu*; Yamaguchi, Aiko*; Segawa, Atsuki*; Ide, Munenori*; Mori, Masatomo*; Oyama, Tetsunari*; Takeyoshi, Izumi*

The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine clinical significance of LAT1 expression and investigate whether LAT1 could be a new therapeutic target for biliary tract cancer. A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, CD98, Ki-67, microvessel density determined by CD34 and p53. Further, anti-tumor activity of LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) was investigated using cholangiocarcinoma cell line. The expression of LAT1 was recognized in 64% of total patients, and closely correlated with CD98 expression, lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. Experiments showed that BCH significantly suppressed the tumor growth and BCH yielded an additive therapeutic efficacy to gemcitabine and 5-FU. A cooperative high expression of LAT1 with CD98 is a promising pathological marker to predict the outcome in biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.