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

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.