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