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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

Outcomes after surgical resection shown by Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS) according to LAT1 and CD98 expression. A statistically significant difference in OS (A) and PFS (B) was observed between patients with high and low LAT1 expression.
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Figure 2: Outcomes after surgical resection shown by Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS) according to LAT1 and CD98 expression. A statistically significant difference in OS (A) and PFS (B) was observed between patients with high and low LAT1 expression.

Mentions: In all patients, the 5-year survival rate and median survival time (MST) for OS were 35.6% and 1073 days, respectively, and the 3-year survival rate and MST for PFS was 45.1% and 840 days, respectively. Because of a postoperative recurrence, 39 patients received systemic chemotherapy using GEM or S-1. Table 3 shows the univariate and multivariate analysis in all patients (n = 139). Univariate analysis revealed that significant variables for OS were resected status, tumor differentiation, lymphatic permeation, vascular invasion, lymph nodes metastasis, LAT1, and Ki-67. Significant prognostic markers for PFS by the univariate analysis included resected status, tumor differentiation, lymphatic permeation, vascular invasion, lymph node metastasis, tumor stage, and LAT1. According to the results of univariate log-rank test, we screened prognostic factors with cut-off of p < 0.05. Multivariate analysis confirmed that lymphatic permeation and a high LAT1 expression, lymphatic permeation and Ki-67 were independent prognostic factors for predicting poor OS, and lymphatic permeation and vascular invasion for poor PFS. Figure 2 shows the Kaplan-Meier survival curve in patients with high and low for LAT1 expression.


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)

Outcomes after surgical resection shown by Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS) according to LAT1 and CD98 expression. A statistically significant difference in OS (A) and PFS (B) was observed between patients with high and low LAT1 expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Outcomes after surgical resection shown by Kaplan-Meier analysis of overall survival (OS) and progression-free survival (PFS) according to LAT1 and CD98 expression. A statistically significant difference in OS (A) and PFS (B) was observed between patients with high and low LAT1 expression.
Mentions: In all patients, the 5-year survival rate and median survival time (MST) for OS were 35.6% and 1073 days, respectively, and the 3-year survival rate and MST for PFS was 45.1% and 840 days, respectively. Because of a postoperative recurrence, 39 patients received systemic chemotherapy using GEM or S-1. Table 3 shows the univariate and multivariate analysis in all patients (n = 139). Univariate analysis revealed that significant variables for OS were resected status, tumor differentiation, lymphatic permeation, vascular invasion, lymph nodes metastasis, LAT1, and Ki-67. Significant prognostic markers for PFS by the univariate analysis included resected status, tumor differentiation, lymphatic permeation, vascular invasion, lymph node metastasis, tumor stage, and LAT1. According to the results of univariate log-rank test, we screened prognostic factors with cut-off of p < 0.05. Multivariate analysis confirmed that lymphatic permeation and a high LAT1 expression, lymphatic permeation and Ki-67 were independent prognostic factors for predicting poor OS, and lymphatic permeation and vascular invasion for poor PFS. Figure 2 shows the Kaplan-Meier survival curve in patients with high and low for LAT1 expression.

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