Elsevier

Lung Cancer

Volume 66, Issue 1, October 2009, Pages 120-126
Lung Cancer

Prognostic significance of l-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in stage I pulmonary adenocarcinoma

https://doi.org/10.1016/j.lungcan.2008.12.015Get rights and content

Abstract

Background

The purpose of this study was to evaluate the prognostic value of l-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in patients with stage I pulmonary adenocarcinoma.

Methods

A total of 139 consecutive patients with pathologic stage I pulmonary adenocarcinoma were retrospectively reviewed. Expression of LAT1, CD98, Ki-67 labeling index, vascular endothelial growth factor (VEGF) and microvessel density (MVD) was also evaluated immunohistochemically and correlated with the prognosis of patients after complete resection of the tumor.

Results

LAT1 and CD98 expression were positive in 23% (32/139) and 22% (31/139), respectively (p = 0.887). LAT1 with CD98 expression was recognized in 15% (21/139). LAT1 expression was significantly correlated with CD98, Ki-67 labeling index, VEGF, and MVD. The 5-year survival rates of LAT1-positive and -negative patients and CD98-positive and -negative patients, were 60.2 and 95.2% (p < 0.0001) and 72.5 and 93.4% (p = 0.0008), respectively. Univariate analysis disclosed that cellular proliferation and MVD in the tumor were significant prognostic factors. However, multivariate analysis confirmed that positive expression of LAT1 and CD98 was an independent factor for predicting a poor prognosis.

Conclusion

The overexpression of LAT1 and CD98 is a pathological factor to predict the prognosis in patients with resectable stage I pulmonary adenocarcinoma.

Introduction

Non-small cell lung cancers (NSCLCs) constitute ∼80% of all lung cancers, with small cell carcinomas making up the remaining 20%. The NSCLC group can be further divided into histologic subtypes with adenocarcinoma, squamous cell carcinoma, and large cell carcinoma being the most common, accounting for 40%, 27%, and 8% of all lung cancers, respectively [1]. Surgical removal is often the choice of treatment in primary lung cancer, but widespread dissemination of the cancer often defeats this mode of treatment. Many pre-operative variables that affect the survival of patients with non-small cell lung cancer have been identified [2]. Search for novel prognostic markers remains an important task for lung cancer diagnosis and treatment.

Amino acid transporters are essential for growth and proliferation in normal and transformed cells [3], [4]. Among amino acid transporters system L is a Na+-independent large and neutral amino acid transport agency [3], [5]. 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 [5], [6], [7]. LAT1 is widely expressed in primary human cancers and several cancer cell lines, where it has been shown to play essential roles in the growth of tumor and the survival of patients [8]. LAT1 requires covalent association with the heavy chain of 4F2 cell surface antigen (CD98) for its functional expression in plasma membrane [5]. Several researchers described the potential role of LAT1 and CD98 expression as a prognostic factor of human neoplasms [8], [9]. We have recently reported that positive expression of LAT1 could be a significant factor to predict poor prognosis of patients with resectable stage I-III NSCLC [10]. The positive rate of LAT1 expression was significantly different between adenocarcinoma (29%) and squamous cell carcinoma (91%), however the LAT1 expression was significantly associated with disease stage, lymphatic permeation, vascular permeation, and pleural involvement in adenocarcinoma [10]. Since the expression profile of LAT1 in adenocarcinoma seems to be different from that of squamous cell carcinoma, clinical significance of LAT1 or CD98 expression should be analyzed according to the histological types.

In this study, LAT1 expression was assessed in the resected tissue specimen and correlated with outcome of patients with stage I pulmonary adenocarcinoma. In addition, LAT1 expression was correlated with CD98, Ki-67 labelling index (LI), and angiogenic markers such as expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD).

Section snippets

Patient

We analyzed 161 consecutive patients with stage I adenocarcinoma who underwent resection lobectomy with mediastinal lymph node dissection at our hospital between June 1997 and May 2004. Twelve patients who received induction of chemotherapy or radiation therapy were excluded. Specimens of 10 patients were not available. A total of 139 patients (61 men, 78 women) were evaluated. The study protocol was approved by the institutional review board.

The age of the patients ranged from 43 to 82 years,

Immunohistochemical findings

LAT1, CD98, Ki-67, VEGF, CD31, and CD34 immunohistochemical staining were evaluated for the surgically resected 139 primary lesions.

Discussion

The present study evaluated the clinical significance of LAT1 and CD98 expression in stage I pulmonary adenocarcinoma. The results of the study clearly demonstrated that the expression of LAT1 and CD98, and the pathologic stage, were a significant independent factor to predict a poor prognosis in patients with stage I pulmonary adenocarcinoma. In cases except non-invasive pure BAC, LAT1 expression and pathologic stage were significant prognostic factors. Moreover, LAT1 expression was closely

Conflicts of interest statement

We, all authors, have no financial or personal relationships with other people or organizations that could inappropriately influence our work.

Acknowledgment

We thank T. Hikino for technical assistance in the immunohistochemical staining of LAT1, CD98, Ki-67, VEGF, CD31, and CD34.

References (31)

  • H.N. Christensen

    Role of amino acid transport and countertransport in nutrition and metabolism

    Physiol Rev

    (1990)
  • J.D. McGivan et al.

    Regulatory and molecular aspects of mammalian amino acid transport

    Biochem J

    (1994)
  • D.L. Oxender et al.

    Evidence for two types of mediation of neutral amino acid transport in Ehrlich cells

    Nature

    (1963)
  • B.C. Fuchs et al.

    Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime?

    Semin Cancer Biol

    (2006)
  • H. Nawashiro et al.

    l-Type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

    Int J Cancer

    (2006)
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