L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer

Fuji Biomedix, Department of Pathology, Kitasato University School of Medicine, Chuou, Japan.
Pathology International (Impact Factor: 1.69). 01/2009; 59(1):7-18. DOI: 10.1111/j.1440-1827.2008.02319.x
Source: PubMed


To find reliable biomarkers for high-grade malignancy, the relationship between immunohistochemical L-type amino-acid transporter 1 (LAT1) expression of biopsy samples, determined with the newly developed monoclonal antibody against human LAT1, and prognosis of patients with prostate cancer, was investigated. The intensity and score of immunohistochemical LAT1 expression of first biopsy samples were assessed using the modified Sinicrope et al. method and were found to be correlated with poor survival for the study group of 114 surgically treated patients as a whole (P = 0.0002 and 0.0270, respectively). LAT1 intensity further had a significant relationship (P = 0.0057) with prognosis in pathological T3 + T4 groups. Multivariate analysis indicated that the LAT1 intensity and score were more reliable prognostic markers, compared with the Gleason score and the Ki-67 labeling index. A relationship of the LAT1 intensity and score with prognosis could also be confirmed in 63 patients with inoperable cancer (P = 0.0070 and <0.0001, respectively). Similarly, significant differences in prognosis were confirmed in clinical T3 + T4 groups (P = 0.0091 and 0.0244, respectively). Moreover, the combination of LAT1 expression and Gleason score was found to have a more reliable correlation with prognosis. Thus, elevated LAT1 expression in prostate cancers is a novel independent biomarker of high-grade malignancy, which can be utilized together with the Gleason score, which is mainly dependent on cellular and structural atypia, to assess prognosis.

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    • "Recent studies have focussed on ASCT2 and LAT1, which are highly expressed in cancer cells (Fuchs and Bode, 2006). The overexpression of LAT1 may be a significant predictor of poor prognosis, and it is closely linked to the aggressiveness and metastasis of various human neoplasms (Nawashiro et al, 2006; Nakanishi et al, 2007; Kaira et al, 2008, 2012; Sakata et al, 2009; Ichinoe et al, 2011; Furuya et al; 2012). "
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    ABSTRACT: Background: ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear. Methods: One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort. Results: ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients. Conclusions: ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.
    British Journal of Cancer 03/2014; 110(8). DOI:10.1038/bjc.2014.88 · 4.84 Impact Factor
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    • "It plays a critical role in the absorption of amino acids from the small intestine, as well as in movement of amino acids across the blood–brain barrier, the placenta, and the proximal tubules of the kidneys [6,7]. Interestingly, LAT1 is associated with cancerous or proliferative cells, and it has been reported that LAT1 is highly expressed in proliferating tissues, many tumor cell lines, and primary human tumors [10-16]. Thus, LAT1 may play a key role in the growth of tumor cells by promoting the uptake of essential amino acids. "
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    ABSTRACT: The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer. To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting. Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors. These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.
    BMC Cancer 10/2013; 13(1):509. DOI:10.1186/1471-2407-13-509 · 3.36 Impact Factor
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    • "These results indicate that the expression of LAT1 is higher in biliary tract cancer than pancreatic cancer. The LAT1 expression is variable in human cancers, and relatively low in adenocarcinoma, for example, 29% in pulmonary adenocarcinoma [12], 22% in prostate cancer [15], 43% in breast cancer [17], and 43% in gastric cancer [16]. LAT1 seemed to be expressed at higher level in biliary tract adenocarcinoma than in adenocarcinoma of the other organs. "
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    ABSTRACT: 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. 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. 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. 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.
    BMC Cancer 10/2013; 13(1):482. DOI:10.1186/1471-2407-13-482 · 3.36 Impact Factor
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