ORIGINAL ARTICLE
Expression of L-type amino acid transporter 1 (LAT1) in neuroendocrine tumors of the lung

https://doi.org/10.1016/j.prp.2008.02.003Get rights and content

Abstract

Amino acid transport systems play an important role in cellular proliferation. L-type amino acid transporter 1 (LAT1) has been associated with tumor growth, and is highly expressed in the established tumor cell lines and primary human neoplasms. In this study, we investigated the expression of LAT1 to evaluate the malignant potential and prognostic significance in neuroendocrine (NE) tumors of the lung.

Twenty-one surgically resected, large cell neuroendocrine carcinomas (LCNEC), 13 small cell lung cancers (SCLC), five atypical carcinoids (AC), and 10 typical carcinoids (TC) were enrolled in the study. LAT1 expression and Ki-67 labeling index of the NE tumors were analyzed by immunohistochemical staining.

LAT1 was overexpressed in 52.4% of the LCNEC, in 46.2% of the SCLC, and in 25% of the AC. LAT1 expression in LCNEC was significantly associated with lymph node metastasis and poor outcome. Moreover, a significant correlation was found between LAT1 expression and Ki-67 in both LCNEC and SCLC.

Expression of LAT1 tended to increase from low-grade to high-grade NE tumors. The present results suggest that LAT1 may play a significant role in cellular proliferation, lymph node metastasis, and poor outcome in patients with NE tumors of the lung.

Introduction

Amino acid transporters are essential for the growth and proliferation of normal and transformed cells [4], [11]. Amino acid transport system L is a Na+-independent large and neutral amino acid transport agency [4], [20]. L-type amino acid transporter 1 (LAT1) is one of the L-type amino acid transporters and transports large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine [11], [20], [28]. LAT1 requires a covalent association with the heavy chain of the 4F2 cell surface antigen (4F2hc) for its functional expression in plasma membrane [20]. It has been reported that in a rat model, LAT1 expression is closely related to the growth of metastatic liver tumor [18]. Previous studies have shown that LAT1 is highly expressed in a variety of tumor cell lines (T24 bladder carcinoma cells, RERF-LC-MA lung small cell carcinoma cells, and HeLa uterine cervical carcinoma cells) and primary human tumors [28]. Nakanishi et al. investigated LAT1 expression in normal lung, atypical adenomatous hyperplasia (AAH), and adenocarcinoma of the lung [16]. They found that the incidence of a positive expression for LAT1 protein increased or tended to increase from low-grade AAH to high-grade AAH to adenocarcinoma [16].

Neuroendocrine (NE) tumors of the lung arise from Kulchitzky cells, which are normally present in the bronchial mucosa and share the common morphologic features of neuroendocrine tumors, including organoid nesting, palisading, rosettes, or a trabecular growth pattern. These tumors are represented by a wide range of pathologic entities [5], [24], [25]. It is now widely recognized that NE tumors of the lung include a spectrum that ranges from low-grade typical carcinoid (TC) to intermediate-grade atypical carcinoid (AC) to high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) [5], [24], [25]. However, their clinicopathologic profiles and relative grade of malignancy have not yet been defined [1], [8], [22]. To ensure the appropriate choice of treatment for patients with various types of NE tumors of the lung, a histology-specific understanding of the clinicopathologic behavior and prognosis is indispensable.

Based on this background, we hypothesized that the incidence of LAT1 expression would increase from low-grade to high-grade to aggressive NE tumors. In this study, we analyzed LAT1 expression of the NE tumors and examined the relationship using clinopathological features, including cellular proliferation determined by the Ki-67 labeling index and prognosis of patients.

Section snippets

Patient selection

A total of 49 patients with NE tumors of the lung (10 TCs, 5 ACs, 21 LCNECs, and 13 SCLCs) were analyzed. They had undergone surgical resection of the tumor at Gunma University Hospital and National Nishi-Gunma Hospital from 2000 to 2006, and were identified in the surgical pathology files of Gunma University Hospital. The clinical records of all patients were reviewed to see the prognosis after surgery. All NE tumors had been diagnosed based on the definitions of the revised WHO classification

Immunohistochemical findings

The results of the immunohistochemical analysis of LAT1 protein expression in pulmonary NE tumors are summarized in Table 1. LAT1 protein was expressed in three types of NE tumors of the lung: LCNEC (11 patients, 52.4%), SCLC (six patients, 46.2%), and AC (one patient, 25%). All patients with TC were negative for LAT1 protein expression. The incidence of LAT1 expression was not significantly different between LCNEC and SCLC (p=0.50). In the present study, no expression of LAT1 protein was

Discussion

This is the first report of a clinicopathological study designed to investigate the expression of LAT1 in NE tumors of the lung. The results indicate that the expression of LAT1 is related to the histological diagnosis. LAT1 expression was observed in 52.4% of LCNEC, in 46.2% of SCLC, and in 25% of AC, whereas TC tumor cells showed no LAT1 immunoreactivity. In cases with LCNEC, LAT1 expression was associated with lymph node metastasis and poor outcome, and was significantly correlated with

Conclusion

LAT1 expression was recognized in LCNEC, SCLC, and AC. The incidence of LAT1 expression tended to increase from low-grade to high-grade NE tumors. LAT1 expression in LCNEC was associated with lymph node metastasis and poor outcome. Although LAT1 expression may increase with the upregulation of metabolic activity and cellular proliferation in NE tumors of the lung, the mechanism of LAT1 overexpression in lung cancer is still unknown. Further investigations are required to verify whether LAT1

Acknowledgments

We thank T. Hikino and F. Hara for their technical assistance in the immunohistochemical staining of LAT1 and Ki-67.

References (28)

  • H. Asamura et al.

    Neuroendocrine neoplasms of the lung: a prognostic spectrum

    J. Clin. Oncol.

    (2006)
  • A.C. Buck et al.

    Ki-67 immunostaining in pancreatic cancer and chronic active pancreatitis: does in vivo FDG uptake correlate with proliferative activity?

    J. Nucl. Med.

    (2001)
  • A. Chairoungdua et al.

    Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein

    J. Biol. Chem.

    (1999)
  • H.N. Christensen

    Role of amino acid transport and countertransport in nutrition and metabolism

    Physiol. Rev.

    (1990)
  • W.A. Cooper et al.

    The surgical spectrum of pulmonary neuroendocrine neoplasms

    Chest

    (2001)
  • T. Inoue et al.

    Detection of malignant tumors: whole-body PET with fluorine 18 α-methyl tyrosine versus FDG-preliminary study

    Radiology

    (2001)
  • International Union Against Cancer (UICC): Lung

  • A. Iyoda et al.

    Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology

    Cancer

    (2001)
  • K. Kaira et al.

    Diagnostic usefulness of fluorine-18-α-methyltyrosine positron emission tomography in combination with 18F-fluorodeoxyglucose in sarcoidosis patients

    Chest

    (2007)
  • K. Kaira et al.

    Fluorine-18-α-methyltyrosine positron emission tomography for diagnosis and staging of lung cancer: a clinicopathological study

    Clin. Cancer Res.

    (2007)
  • Y. Kanai et al.

    Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98)

    J. Biol. Chem.

    (1998)
  • D.K. Kim et al.

    Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells

    Biochim. Biophys. Acta

    (2002)
  • H. Kobayashi et al.

    Expression of L-type amino acid transporter 1 (LAT1) in esophageal carcinoma

    J. Surg. Oncol.

    (2005)
  • H. Matsuo et al.

    Expression of a system L neutral amino acid transporter at the blood-brain barrier

    Neuroreport

    (2000)
  • Cited by (62)

    • PET/CT Variants and Pitfalls in Prostate Cancer: What You Might See on PET and Should Never Forget

      2021, Seminars in Nuclear Medicine
      Citation Excerpt :

      A single case of incidental neuroendocrine tumour showing Fluciclovine uptake in lungs and liver (later confirmed by octreotide SPECT/CT) in a patient studied for recurrence of PC has been reported in the literature.73 This phenomenon can be explained by the overexpression of amino acid transport LAT-1 (targeted from Fluciclovine) in some neuroendocrine tumors, such as pheochromocytoma, medullary thyroid carcinoma and lung carcinoid.74–76 Due to its little uptake in the kidneys (lower than FDG), Fluciclovine tracer has been studied in evaluating renal masses.

    • Molecular characteristics supporting L-Type amino acid transporter 1 (LAT1)-mediated translocation

      2021, Bioorganic Chemistry
      Citation Excerpt :

      LAT1 is found for the most part in the brain, testis, and placenta [1] It is also highly expressed at the BBB [8] and in various tumor cells including breast, prostate, and colorectal cancer and glioblastoma multiforme (GBM) [2,9–13]. In cancer cells, high expression levels of LAT1 correlates with cancer progression and poor prognosis [10,14–18]. However, it is possible to reduce the growth of cancer cells by inhibiting the function of LAT1 [19–23].

    • Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma

      2019, Human Pathology
      Citation Excerpt :

      PPC is recognized as a rare tumor with a dismal outcome, and little is known about any promising targets of this disease; however, LAT1 may be an attractive target for patients with PPC. Recently, the frequency of LAT1 expression has been elucidated in thoracic neoplasms, such as NSCLC, pulmonary neuroendocrine tumor, malignant pleural mesothelioma, and thymic epithelial tumors [11,20-22]. Positive expression rates of LAT1 were identified in 51% of 321 NSCLCs, 46.2% of 13 small cell lung cancers, 52.4% of 21 large cell neuroendocrine carcinomas, 75% of 8 thymic carcinomas, and 50% of 21 malignant pleural mesotheliomas.

    View all citing articles on Scopus
    View full text