Expression of N-myc downstream regulated gene 1 (NDRG1) in central neurocytoma

Abstract

N-myc downstream regulated gene 1 (NDRG1), also known as Cap43, Drg-1, and rit42, is expressed in various normal tissues and cancers, in which it is often associated with a favorable prognosis. It also plays a critical role in central nervous system development, with NDRG1 deficiency resulting in neural defects in mice. Central neurocytoma (CN) is a relatively rare tumor of the neurocytes in the brain, which occurs mainly in young adults. In the present study, we found that tissue samples from four patients with CN had both nuclear and cytoplasmic/membranous expression of NDRG1 protein in highly differentiated CN tumor cells. NDRG1 was also expressed in intratumoral microvessels. Immunohistochemical study of serial sections from the same patients revealed a marked association between the expression pattern of NDRG1 and that of neuron-specific enolase, a tumor differentiation marker. The data presented in this study suggest that NDRG1 could be considered a potential differentiation marker for CN.

Introduction

N-myc downstream regulated gene 1 (NDRG1), also known as differentiation-related gene 1 (Drg1), Cap43, and rit42, is a gene strongly induced by hypoxia and metal ions.[1], [2] Expression of NDRG1 has been reported in various normal tissues, including the nervous systems of mice.³ Accordingly, targeted disruption of NDRG1 results in impaired development of the murine nervous system.⁴ This indicates that the NDRG1 gene plays a vital role during embryonic development of the nervous system. The expression pattern of NDRG1 in various parts of the nervous system is also noteworthy. For example, in the cerebrum, in contrast to other parts of the brain, NDRG1 protein is reportedly localized in oligodendrocytes.⁵

In contrast to normal tissues, NDRG1 is usually downregulated in highly proliferating tumor cells. For this reason, the gene has also been called ‘reduced in tumor 42 kDa’ or rit42.⁶ NDRG1 is known to be expressed in various human malignancies.[7], [8], [9], [10] Expression of this gene indicates a favorable prognosis in some cancers, such as breast and colon cancers,[7], [8] but a poor prognosis in others, such as hepatocellular carcinoma and endometrial carcinoma.[9], [10] However, NDRG1 status in tumors originating from the nervous system has not been evaluated in most patients. We are engaged in evaluating the involvement of NDRG1 in various brain tumors.

In 1982, Hassoun et al. reported two patients with differentiated neuroblastoma with the clinical and light microscopic appearance of intraventricular oligodendroglioma.¹¹ They named this tumor ‘central neurocytoma’ (CN) and defined its characteristics in a later study.¹² CN, which occurs mainly in young adults, is a relatively rare tumor of the central nervous system (representing 0.25–0.5% of all intracranial tumors), and is usually located in the cerebral ventricles.¹³ According to the WHO classification, CN is ‘a tumor composed of round and uniform cells with neuronal differentiation, normally located in the lateral ventricles near Monro foramina’.[13], [14] CN is generally considered a tumor with neurocytic differentiation and a good clinical process.[15], [16]

Primary brain tumors arise from three main groups of cells found in normal brain tissue: glial, oligodendroglial, and neuronal cells. Tumors that develop from each group frequently have similar cellular markers to the originating cells. Therefore, a marker such as glial fibrillary acidic protein, which is expressed in normal glial cells, is usually used in the pathological diagnosis of gliomas and astrocytomas.

In the present study, we examined the expression of NDRG1 in CN tumor cells, which originate from neuronal cells. We investigated NDRG1 expression in CN samples from four patients diagnosed with this cancer. Furthermore, we investigated the association between NDRG1 and neuron-specific enolase (NSE), a neuronal differentiation marker.