Noboru Oriuchi

Fukushima Medical University, Hukusima, Fukushima, Japan

Are you Noboru Oriuchi?

Claim your profile

Publications (260)680.39 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A PET tracer for tumor imaging, 3-18F-l-α-methyl-tyrosine ([18F]FAMT), has advantages of high cancer-specificity and low physiological background. In clinical studies, FAMT-PET has been proved useful for the detection of malignant tumors and their differentiation from inflammation and benign lesions. The tumor specific uptake of FAMT is due to its high-selectivity to cancer-type amino acid transporter LAT1 among amino acid transporters. In [18F]FAMT PET, kidney is the only organ that shows high physiological background. To reveal transporters involved in renal accumulation of FAMT, we have examined [14C]FAMT uptake on the organic ion transporters responsible for the uptake into tubular epithelial cells. We have found that OAT1, OAT10 and OCTN2 transport [14C]FAMT. The [14C]FAMT uptake was inhibited by probenecid, furosemide and ethacrynic acid, consistent with the properties of the transporters. The amino acid uptake inhibitor, 2-amino-2-norbornanecarboxylic acid (BCH), also inhibited the [14C]FAMT uptake, whereas OCTN2-mdediated [14C]FAMT uptake was Na+-dependent. We propose that FAMT uptake by OAT1, OAT10 and OCTN2 into tubular epithelial cells could contribute to the renal accumulation of FAMT. The results from this study would provide clues to the treatments to reduce renal background and enhance tumor uptake as well as to designing PET tracers with less renal accumulation.
    Preview · Article · Jan 2016 · Journal of Pharmacological Sciences
  • [Show abstract] [Hide abstract]
    ABSTRACT: 3-(18) F-l-α-methyl-tyrosine ([(18) F]FAMT), a PET probe for tumor imaging, has advantages of high cancer-specificity and lower physiologic background. FAMT-PET has been proved useful in clinical studies for the prediction of prognosis, the assessment of therapy response and the differentiation of malignant tumors from inflammation and benign lesions. The tumor uptake of [(18) F]FAMT in PET is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L upregulated in cancers. In this study, to assess the transporter-mediated mechanisms in FAMT uptake by tumors, we examined amino acid transporters for FAMT transport. We synthesized [(14) C]FAMT and measured its transport by human amino acid transporters expressed in Xenopus oocytes. The transport of FAMT was compared with that of l-methionine, a well-studied amino acid PET probe. The significance of LAT1 in FAMT uptake by tumor cells was confirmed by siRNA knockdown. Among amino acid transporters, [(14) C]FAMT was specifically transported by LAT1, whereas l-[(14) C]methionine was taken up by most of the transporters. Km of LAT1-mediated [(14) C]FAMT transport was 72.7μM, similar to that for endogenous substrates. Knockdown of LAT1 resulted in the marked reduction of [(14) C]FAMT transport in HeLa S3 cells, confirming the contribution of LAT1 in FAMT uptake by tumor cells. FAMT is highly specific to cancer-type amino acid transporter LAT1, which explains cancer-specific accumulation of [(18) F]FAMT in PET. This, vice versa, further supports the cancer-specific expression of LAT1. This study has established FAMT as a LAT1-specific molecular probe to monitor the expression of a potential tumor biomarker LAT1. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Cancer Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: Amino acid transporters are essential for the growth, progression and the pathogenesis of various cancers. However, it remains obscure about the clinicopathological significance of L-type amino acid transporter 1 (LAT1) and system ASC amino acid transporter 2 (ASCT2) for patients with human ovarian tumors. The aim of this study is to elucidate the prognostic role of these amino acid transporters in ovarian tumor. One-hundred forty-two patients with surgically resected ovarian tumors were analyzed by immunohistochemistry. Expression of LAT1, ASCT2, CD98, Ki-67 and microvessel density (MVD) determined by CD34 were evaluated using specimens of the resected tumors. LAT1 and ASCT2 were positively expressed in 39% and 53%, respectively, of ovarian tumors (n=142) and 50% and 57%, respectively, of epidermal ovarian cancers (n=107). A positive LAT1 expression was closely correlated with the expression for ASCT2 and CD98, and cell proliferation (Ki-67) in ovarian cancer. By multivariate analysis, LAT1 was clarified as a significant independent marker for predicting a poor overall survival (OS). The expression of LAT1 could clearly discriminate between epidermal ovarian cancer and borderline malignancy. The expression level of LAT1 within ovarian cancer cells varied among serous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma and mucinous adenocarcinoma and we found LAT1 expression was higher in clear cell adenocarcinoma than other histological types. LAT1 is highly expressed in various ovarian tumors and a positive LAT1 expression can serve as a significant independent factor for predicting a poor OS in patients with epidermal ovarian cancer.
    No preview · Article · Aug 2015 · American Journal of Translational Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: Amino acid transporters play a crucial role in the development and invasiveness of cancer cells. However, it remains unclear whether or not the expression of L-type amino acid transporter 1 (LAT1) has prognostic significance in patients with cutaneous melanoma. A total of 128 patients with cutaneous melanoma were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, CD98, Ki-67, and microvessel density determined by CD34 and p53. We also analyzed 30 specimens of patients with melanocytic nevi as negative controls. LAT1 and CD98 were highly expressed in 58% (75/128) and 75% (97/128), respectively. The rates of positivity for LAT1 in the melanocytic nevi were 0% (0/30). The expression of LAT1 was associated significantly with tumor thickness, T factor, CD98 expression, cell proliferation (Ki-67), and microvessel density (CD34). By Spearman's rank test, LAT1 expression was correlated with CD98, Ki-67, and CD34. By univariate analysis, tumor thickness, ulceration, disease staging, LAT1, and CD34 showed a significant relationship with overall survival and disease-free survival. Furthermore, a multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting a poor prognosis. This study had a small sample size. LAT1 can serve as a significant prognostic factor to predict a poor outcome and it may therefore play an important role in the aggressiveness of cutaneous melanoma.
    No preview · Article · Jul 2015 · Melanoma research
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study is to evaluate the clinicopathological significance of L-type amino acid transporter 1 (LAT1) expression in patients with advanced laryngeal squamous cell carcinoma (LSCC). A total of 73 patients with advanced LSCC were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, 4F2hc, system ASC amino acid transporter-2 (ASCT2), cell proliferation by Ki-67, microvessel density (MVD) determined by CD34 and p53. A positive LAT1, 4F2hc and ASCT2 expression (staining more than a quarter) in the primary sites were recognized in 85, 80 and 45 %, respectively, and a high LAT1, 4F2hc and ASCT2 expression (staining more than a half) yielded 48, 31 and 18 %, respectively. High expression of LAT1 was significantly associated with lymph node metastasis, 4F2hc, ASCT2, Ki-67 and p53. The expression of LAT1 was significantly correlated with ASCT2, 4F2hc, cell proliferation, and MVD. By univariate analysis, there was no statistically significant relationship between LAT1 expression and prognosis in advanced LSCC. LAT1, 4F2hc and ASCT2 were highly expressed in patients with advanced laryngeal cancer. Our study suggests that the expression of LAT1 plays a crucial role in the metastasis and tumor progression in advanced LSCC.
    No preview · Article · May 2015 · Pathology & Oncology Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD147 functions as an induction of matrix metalloproteinases and tumor angiogenesis, and is highly expressed in various malignant neoplasms. Recently, CD147 is shown to form a complex with amino acid transporters such as L-type amino acid transporter (LAT1), system ASC amino acid transporter-2 (ASCT2) and 4F2hc as a heavy chain of LAT1. It remains unknown about the existence of these complexes in patients with pancreatic cancer. The aim of this study is to investigate the relationship between CD147 and these amino acid transporters. Ninety-seven patients with pancreatic cancer were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, Ki-67, microvessel density (MVD) determined by CD34, p-AKT, and p-mTOR. CD147 was highly expressed in 23% (22/97) of patients. A high expression of CD147 is significantly associated with N factor, LAT1, ASCT2, Ki-67, VEGF and p-mTOR. A high CD147 expression was identified as a significant prognostic predictor by univariate survival analysis. The coexpression of CD147 and LAT1, and that of CD147 and 4F2hc yielded a significantly worse prognosis than the single expression of LAT1, and that of 4F2hc, respectively. CD147 revealed a significant relationship with the expression level of LAT1 and ASCT2, correlated with tumor proliferation, angiogenesis and mTOR signaling.
    No preview · Article · Apr 2015 · American Journal of Translational Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman's rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 (LAT1, r=0.562, P<0.001), Ki-67 (r=0.230, P=0.006) and CD34 (r=0.290, P=0.005). Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.
    No preview · Article · Dec 2014 · Hepatobiliary & pancreatic diseases international: HBPD INT
  • [Show abstract] [Hide abstract]
    ABSTRACT: PurposeAmino acid transporters play an important role in the tumor progression and survival of cancer cells. But, it remains unclear about the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino acid transporter-2 (ASCT2) and xCT expression in patients with hepatocellular carcinoma (HCC). The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC.Material and Methods We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34.ResultsLAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and α-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery.ConclusionLAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery.
    No preview · Article · Oct 2014 · Hepatology Research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Effective treatments for malignant neuroendocrine tumors are under development. While iodine-131 metaiodobenzylguanidine ((131)I-MIBG) radiotherapy has been used in the treatment of malignant neuroendocrine tumors, there are few studies evaluating its therapeutic effects and safety in a multicenter cohort. In the current study, we sought to evaluate the effects and safety of (131)I-MIBG therapy for conditions including malignant pheochromocytoma and paraganglioma within a multicenter cohort. Forty-eight malignant neuroendocrine tumors (37 pheochromocytoma and 11 paraganglioma) from four centers underwent clinical (131)I-MIBG radiotherapy. The tumor responses were observed before and 3 to 6 months after the (131)I-MIBG radiotherapy in accordance with RECIST criteria. We also evaluated the data for any adverse effects. The four centers performed a total of 87 (131)I-MIBG treatments on 48 patients between January 2000 and March 2009. Of the treatments, 65 were evaluable using RECIST criteria. One partial response (PR), 40 stable disease (SD), and 9 progressive disease (PD) in malignant pheochromocytoma were observed after each treatment. Fourteen SD and one PD were observed in paraganglioma. Patients with normal hypertension (systolic blood pressure (BP) > 130 mmHg) showed significantly reduced systolic BP after the initial follow-up (n=10, 138.1±8.2 to 129.5±13.5 mmHg, P=0.03). In adult neuroendocrine tumors with a treatment-basis analysis, there were side effects following 41 treatments (47.1%) and most of them (90.2%) were minor. In this multicenter registry, PR or SD was achieved in 84.6% of the treatment occasions in adult neuroendocrine tumors through (131)I-MIBG radiotherapy. This indicated that most of the (131)I-MIBG radiotherapy was performed safely without significant side effects.
    Preview · Article · Sep 2014 · Endocrine Journal
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: L-type amino-acid transporter 1 (LAT1) plays a key role in cell growth and survival. To determine the prognostic significance of LAT1 in multiple myeloma (MM), we investigated the expression of LAT1 and its functional subunit, 4Fc heavy chain (CD98), on myeloma cells by immunohistochemistry in 100 newly diagnosed MM patients. High expression (moderate or strong staining intensity) of LAT1 and CD98 was detected in 56% and 45% of patients, respectively. The LAT1 expression score was positively correlated with Ki-67 index (r=0.631, p<0.001), and there was a statistically significant difference in Durie-Salmon stage between patients with high and low LAT1 expression (p=0.03). In 43 patients treated with melphalan and prednisolone, overall response rate was significantly higher in the high LAT1 expression group (60.0%) than in the low LAT1 expression group (17.6%) (p=0.03). Multivariate analysis confirmed that high expression of LAT1 was a significant prognostic factor for predicting poor overall survival independently from the International staging system (both p=0.01). Here, we show that the overexpression of LAT1 is significantly associated with high proliferation and poor prognosis in newly diagnosed MM patients. Thus, LAT1 may be a promising pathological marker for identifying high-risk MM.This article is protected by copyright. All rights reserved.
    Preview · Article · Sep 2014 · Cancer Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Both L-type amino acid transporter 1 (LAT1) and CD98 are strongly expressed in primary human cancer and play essential roles in tumor growth. We studied the clinicopathological significance of LAT1 and CD98 expression in hypopharyngeal squamous cell carcinoma (SCC). Methods: A total of 70 patients with stage III/IV disease were retrospectively reviewed. Immunohistochemical staining of tumor sections was used to examine LAT1, CD98, Ki-67, CD34, and p53. Results: High LAT1 and CD98 expression were noted in 60.0% and 47.1%, respectively (p = .174). A statistically significant correlation was recognized between LAT1 and CD98 expression and both expressions were closely associated with tumor cell proliferation. Although LAT1 expression was not significantly associated with poor survival, multivariate analysis revealed high CD98 expression to be an independent prognostic factor for predicting a poor outcome. Conclusion: CD98 is a promising prognostic marker for predicting outcomes after surgical treatment in patients with advanced hypopharyngeal SCC. © 2014 Wiley Periodicals, Inc. Head Neck, 2014.
    No preview · Article · Aug 2014 · Head & Neck
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: ASC amino acid transporter-2 (ASCT2) is highly expressed in cancer cells. However, the clinicopathological significance of ASCT2 expression in pancreatic cancer remains unclear. The aim of this study was to investigate the clinical significance of ASCT2 expression in pancreatic cancer. Methods and results: Ninety-seven patients with surgically resected pancreatic ductal adenocarcinoma were evaluated. Tumour sections were stained by immunohistochemistry for ASCT2, Ki67, CD34 (to determine microvessel density), phospho-AKT (p-AKT) and phospho-mammalian target of rapamycin (p-mTOR) expression. ASCT2 was expressed in 54% (52/97) of tumours. Statistically significant differences in patient age, T stage, N stage, lymphatic permeation, vascular invasion, Ki67, and CD34 and p-mTOR expression were observed between tumours with and without ASCT2 expression. Multivariate analysis confirmed that vascular invasion, ASCT2 expression and Ki67 expression were independent predictive factors for a poorer prognosis. Conclusions: ASCT2 expression plays an important role in tumour cell growth, and is a promising pathological marker for predicting a worse outcome in pancreatic cancer.
    No preview · Article · May 2014 · Histopathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino-acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer. Methods: Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53. Results: L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. Conclusions: L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer.
    Preview · Article · Apr 2014 · British Journal of Cancer
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: 18F-FAMT as an amino-acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. 18F-FAMT is accumulated in tumour cells solely via L-type amino-acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of 18F-FAMT uptake in patients with oesophageal cancer. Methods: From April 2008 to December 2011, 42 patients with oesophageal cancer underwent both 18F-FAMT PET/CT and 18F-FDG PET/CT before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. In vitro experiments were performed to examine the mechanism of 18F-FAMT uptake. Results: High uptake of 18F-FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. In vitro experiments revealed that 18F-FAMT was specifically transported by LAT1. Conclusions: The uptake of 18F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of 18F-FAMT accumulation.
    Preview · Article · Mar 2014 · British Journal of Cancer
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2014 · British Journal of Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study is to investigate the underlying biologic mechanisms of 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake on positron emission tomography (PET) in non-small cell lung cancer (NSCLC). One-hundred forty patients with NSCLC who underwent (18)F-FDG PET were included in the study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), GLUT3, hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessels (CD34), epidermal growth factor receptor (EGFR), and molecules relevant to PI3K/Akt/mTOR signaling pathway (PTEN, p-Akt, p-mTOR and p-S6). We also conducted in vitro studies of (18)F-FDG uptake and mTOR inhibition in NSCLC cells. High (18)F-FDG uptake was significantly associated with poor prognosis in NSCLC patients. (18)F-FDG uptake was significantly correlated with GLUT1, hexokinase I, HIF-1α, VEGF, CD34, p-Akt, p-mTOR and EGFR. PTEN expression showed inverse correlation with (18)F-FDG uptake. In in vitro study, (18)F-FDG uptake was markedly decreased by the inhibition of GLUT1 and GLUT1 upregulation by the induction of HIF-1α increased the (18)F-FDG uptake. Inhibition of both mTOR complex1 (mTORC1) and mTORC2 suppressed cell growth, but activity of mTORC1 regulated the (18)F-FDG uptake. NCI-H1650 cells with PTEN loss showed the highest (18)F-FDG uptake and the least sensitivity to mTOR inhibitors. The amount of (18)F-FDG accumulation is associated with molecules relevant to glucose metabolism, hypoxia, angiogenesis and mTOR signaling pathway. Especially, PTEN status may affect not only (18)F-FDG uptake but also effect of mTOR inhibitors on the growth of NSCLC.
    No preview · Article · Dec 2013 · Lung cancer (Amsterdam, Netherlands)
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Carcinoembryonic antigen (CEA) is an attractive target molecule of radioimmunotherapy (RIT). To enhance RIT's therapeutic efficacy, the fractionation of radiolabeled antibody doses is an attractive strategy. In this study, a fully human anti-CEA monoclonal antibody (mAb) C2-45 was selected by virtue of its lack of immunogenicity, and the effectiveness of fractionated RIT with yttrium-90 ((90)Y)-labeled mAb C2-45 was evaluated. In LS180 tumor-bearing mice, indium-111 ((111)In)-labeled mAb C2-45 showed high and persistent tumor accumulation. Therapeutic studies were performed with single doses of (90)Y-mAb C2-45 (100 or 200 μCi) or double doses of 100 μCi (90)Y-mAb C2-45 at different intervals (5, 10, and 15 days). All (90)Y-mAb C2-45-treated mice showed inhibition of tumor progression, while the time to tumor progression was much longer in both the 200-μCi-treated group and the double 100-μCi-treated group than in the single 100-μCi-treated group. The therapeutic effect of the double 100 μCi administration at days 0 and 15 lasted significantly longer than that in the other treatment groups. These findings indicate that (90)Y-mAb C2-45 may be a promising agent for the treatment of CEA-positive cancer and that the fractionation of (90)Y-labeled antibody doses could enhance the therapeutic effect if performed according to an appropriate protocol.
    No preview · Article · Dec 2013 · Cancer Biotherapy & Radiopharmaceuticals
  • Source
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Oct 2013 · BMC Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: L-[3-(18)F]-α-Methyltyrosine ((18)F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of (18)F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of (18)F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. The study group comprised 68 OSCC patients who underwent both (18)F-FAMT and (18)F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. The sensitivity of primary tumour detection by (18)F-FAMT and (18)F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of (18)F-FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for (18)F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of (18)F-FAMT were significantly higher than those of (18)F-FDG. The uptake of (18)F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. (18)F-FAMT PET showed higher specificity for detecting malignant lesions than (18)F-FDG PET. The uptake of (18)F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation.
    No preview · Article · Jun 2013 · European Journal of Nuclear Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: The expression of L-type amino acid transporter 1 (LAT1) is correlated with tumor cell growth and survival. However, the clinicopathological significance of LAT1 expression in adenoid cystic carcinoma (ACC) remains to be elucidated. The aim of this study is to investigate the clinicopathological significance of LAT1 expression in ACC. A total of 30 patients with ACC were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, p53, and CD98, and cell proliferation and microvessel density (MVD) were determined by Ki-67 and CD34, respectively. High LAT1 and CD98 expression were observed in 27 % (8/30) and 23 % (7/30) of samples, respectively (p > 0.999). The high expression of LAT1 was significantly correlated with cell proliferation (Ki-67) and the cell cycle regulator p53. By univariate analysis, solid histological pattern, maxillary tumor site, LAT1, CD98, Ki-67 and p53 were significantly associated with poor prognosis. Multivariate analysis demonstrated that the high expression of LAT1 was an independent prognostic factor for predicting poor prognosis after surgical resection. LAT1 is a promising clinical marker to predict the outcome after surgery in patients with ACC.
    No preview · Article · Mar 2013 · Pathology & Oncology Research

Publication Stats

4k Citations
680.39 Total Impact Points

Institutions

  • 2016
    • Fukushima Medical University
      • Center for Clinical Research
      Hukusima, Fukushima, Japan
  • 1991-2015
    • Gunma University
      • • Graduate School of Medicine
      • • Department of Neurosurgery
      • • School of Medicine
      Maebashi, Gunma, Japan
  • 2013
    • Saku Central Hospital
      Сакура, Chiba, Japan
  • 2010-2011
    • Shizuoka Cancer Center
      • Division of Drug Discovery and Development
      Sizuoka, Shizuoka, Japan
  • 2002
    • Yokohama City University
      • Department of Radiology (YCUH)
      Yokohama, Kanagawa, Japan
  • 2001
    • Department of Nuclear Medicine
      Nyitra, Nitriansky, Slovakia
  • 1999-2001
    • Nippon Medical School
      • Department of Pathology
      Edo, Tōkyō, Japan
  • 2000
    • National Institute of Radiological Sciences
      • Molecular Imagining Center
      Tiba, Chiba, Japan
  • 1998-2000
    • University of Texas MD Anderson Cancer Center
      • Department of Nuclear Medicine
      Houston, Texas, United States
  • 1990
    • Niigata Teishin Hospital
      Niahi-niigata, Niigata, Japan