title: Clinical significance of L-type amino acid transporter 1 expression as a prognostic marker and potential of new targeting therapy in biliary tract cancer.
abstract: BACKGROUND
  The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer.
  
  
  METHODS
  A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line.
  
  
  RESULTS
  In total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU.
  
  
  CONCLUSIONS
  High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, Japan. kkaira1970@yahoo.co.jp.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kaira
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sunose
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ohshima
authors.forename: Noriko S
authors.initials: NS
authors.lastname: Ishioka
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Arakawa
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sunaga
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Shimizu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tominaga
authors.forename: Noboru
authors.initials: N
authors.lastname: Oriuchi
authors.forename: Hideaki
authors.initials: H
authors.lastname: Itoh
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Aiko
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Atsuki
authors.initials: A
authors.lastname: Segawa
authors.forename: Munenori
authors.initials: M
authors.lastname: Ide
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Oyama
authors.forename: Izumi
authors.initials: I
authors.lastname: Takeyoshi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D027261:Fusion Regulatory Protein-1 / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015999:Multivariate Analysis; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D027261:Fusion Regulatory Protein-1; D027283:Large Neutral Amino Acid-Transporter 1; D003841:Deoxycytidine; D005472:Fluorouracil; D000093542:Gemcitabine