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

Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Yamaguchi A, Segawa A, Ide M, Mori M, Oyama T, Takeyoshi I - BMC Cancer (2013)

Bottom Line: 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.Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, Japan. kkaira1970@yahoo.co.jp.

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.

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Related in: MedlinePlus

Immunohistochemical staining of tissue from a 79-years old man with extrahepatic cholangiocarcinoma (A) and a 66-years old woman with Xanthogranulomatous chlecystitis as control group (B). Immunostaining of LAT1 demonstrates a membranous immunostaining pattern in cholangiocarcinoma, but there was no evidence of LAT1 staining in xanthogranulomatous chlecystitis.
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Figure 1: Immunohistochemical staining of tissue from a 79-years old man with extrahepatic cholangiocarcinoma (A) and a 66-years old woman with Xanthogranulomatous chlecystitis as control group (B). Immunostaining of LAT1 demonstrates a membranous immunostaining pattern in cholangiocarcinoma, but there was no evidence of LAT1 staining in xanthogranulomatous chlecystitis.

Mentions: The immunohistochemical analysis was performed on the 139 primary lesions with cholangiocarcinoma and 16 resected lesions with biliary benign diseases. Figure 1 represents the immunohistochemical staining of LAT1 expression. LAT1 immunostaining was detected in carcinoma cells in tumor tissues and localized predominantly on their plasma membrane. All positive cells revealed strong membranous LAT1 immunostaining. Cytoplasmic staining was rarely evident. The high expression rate and average scoring of LAT1 were compared according to tumor location (Additional file 2: Table S2, online only). In total patients, the high expression rate and average scoring of LAT1 were recognized in 64.0% and 2.7 ± 0.9, respectively.


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

Kaira K, Sunose Y, Ohshima Y, Ishioka NS, Arakawa K, Ogawa T, Sunaga N, Shimizu K, Tominaga H, Oriuchi N, Itoh H, Nagamori S, Kanai Y, Yamaguchi A, Segawa A, Ide M, Mori M, Oyama T, Takeyoshi I - BMC Cancer (2013)

Immunohistochemical staining of tissue from a 79-years old man with extrahepatic cholangiocarcinoma (A) and a 66-years old woman with Xanthogranulomatous chlecystitis as control group (B). Immunostaining of LAT1 demonstrates a membranous immunostaining pattern in cholangiocarcinoma, but there was no evidence of LAT1 staining in xanthogranulomatous chlecystitis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016614&req=5

Figure 1: Immunohistochemical staining of tissue from a 79-years old man with extrahepatic cholangiocarcinoma (A) and a 66-years old woman with Xanthogranulomatous chlecystitis as control group (B). Immunostaining of LAT1 demonstrates a membranous immunostaining pattern in cholangiocarcinoma, but there was no evidence of LAT1 staining in xanthogranulomatous chlecystitis.
Mentions: The immunohistochemical analysis was performed on the 139 primary lesions with cholangiocarcinoma and 16 resected lesions with biliary benign diseases. Figure 1 represents the immunohistochemical staining of LAT1 expression. LAT1 immunostaining was detected in carcinoma cells in tumor tissues and localized predominantly on their plasma membrane. All positive cells revealed strong membranous LAT1 immunostaining. Cytoplasmic staining was rarely evident. The high expression rate and average scoring of LAT1 were compared according to tumor location (Additional file 2: Table S2, online only). In total patients, the high expression rate and average scoring of LAT1 were recognized in 64.0% and 2.7 ± 0.9, respectively.

Bottom Line: 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.Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, Japan. kkaira1970@yahoo.co.jp.

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.

Show MeSH
Related in: MedlinePlus