LAT-1 and GLUT-1 Carrier Expression and Its Prognostic Value in Gastroenteropancreatic Neuroendocrine Tumors.

Julian Aragones,Concepción Blanco-Carrera,Mónica Marazuela,Ana Serrano-Somavilla,José Luis Muñoz de Nova,José Manuel Cameselle-Teijeiro,Elena Martín-Pérez,Rogelio García-Centeno,Miguel Sampedro-Núñez,José Ángel Díaz,Antonio Bouthelier,Magdalena Adrados,Rebeca Martínez-Hernández,José Manuel Cabezas-Agricola

doi:10.3390/cancers12102968

Abstract

Simple SummaryGastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent about 70% of all NETs; however, improvement in their outcomes has yet to be achieved. Here, we aimed to analyze the role of metabolic players such as the amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing mechanism Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF), in gastroenteropancreatic neuroendocrine tumors (GEP-NET). We also aimed to correlate them with tumor malignancy and progression. We confirmed that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. Our results suggest that these biomarkers could have a potential role in NET pathophysiology which might be related to their proliferation and metastatic capacity.Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors.

Highlights

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise an eclectic group of infrequent neoplasms that arise from enterochromaffin epithelial cells or from a variety of other neuroendocrine (NE) cells
Tumors with metastases at diagnosis displayed increased LAT-1 and glucose transporter 1 (GLUT-1) and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and glucose membrane transporter (GLUT)-1, are increased in gastroenteropancreatic neuroendocrine tumors (GEP-NET), whereas pVHL is decreased
We began by applying a tissue microarray (TMA) approach to investigate immunohistochemical expression of LAT-1, GLUT-1, and pVHL in a large set of GEP-NET tumor samples

Summary

Introduction

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise an eclectic group of infrequent neoplasms that arise from enterochromaffin epithelial cells or from a variety of other neuroendocrine (NE) cells (e.g., alpha or beta cells, among others). Primary lesions of GEP-NETs tend to be found in the gastric mucosa, small and large intestine, rectum, and pancreas. Clinical guidelines have clearly defined disease stage by the tumor, lymph node, and metastasis (TNM) classification and tumor grade as the two major independent prognostic parameters for GEP-NET diagnosis [3,4]. While surgical resection of malignant tissue is the leading treatment option for GEP-NETs, a complete cure is rarely possible and several therapies are used, including targeted therapies (somatostatin analogues, everolimus, and sunitinib) and/or chemotherapy. Characterization of biomarkers of prognosis and therapeutic response for these neoplasms is imperative [5]

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