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We thank Francisca Molina-Jimenez from the Instituto Universitario Princesa for kindly giving technical assistance with confocal microscopy and Manolo Gomez for English corrections of the manuscript. We also warmly thank all the participants included in the study for their selfless participThis work was supported by the following grants: Proyectos de Investigacion en Salud (FIS) PIE13-0041, PI16-02091 and PI19-00584 (funded by Instituto de Salud Carlos III), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), GETNE G1707 and GCI1901 (funded by Grupo Espanol de Tumores Neuroendocrinos y Endocrinos) and cofinanced by FEDER funds to M.M. Proyectos de Investigacion en Salud (FIS) PI19/01316-FEDER (funded by Instituto de Salud Carlos III), given to J.C.T. Grants from the Ministerio de Economia y Competitividad (SAF2016-76815 and SAF2017-90794-REDT), and Fundacio La Marato de TV3 (534/C/2016) ceded to J.A.ation. We also thank the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER GCV14/ER/12) for their support.

Analysis of institutional authors

Sampedro-Nunez, MiguelAuthorMartinez-Hernandez, RebecaAuthorMartin-Perez, ElenaAuthorMuÑoz De Nova, Jose LuisAuthorAragones, JulianAuthorMarazuela, MonicaCorresponding Author

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Article

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

Publicated to:Cancers. 12 (10): 1-18 - 2020-10-01 12(10), DOI: 10.3390/cancers12102968

Authors: Sampedro-Nunez, Miguel; Bouthelier, Antonio; Serrano-Somavilla, Ana; Martinez-Hernandez, Rebeca; Adrados, Magdalena; Martin-Perez, Elena; Munoz de Nova, Jose Luis; Cameselle-Teijeiro, Jose Manuel; Blanco-Carrera, Concepcion; Cabezas-Agricola, Jose Manuel; Diaz, Jose angel; Garcia-Centeno, Rogelio; Aragones, Julian; Marazuela, Monica;

Affiliations

Autonomous Univ Madrid, Res Inst Princesa IP, Res Unit, Hosp Santa Cristina, Madrid 28009, Spain - Author
Carlos III Hlth Inst, CIBER Enfermedades Cardiovasc CIBERCV, Madrid 28029, Spain - Author
Hosp Univ Gregorio Maranon, Serv Endocrinol, Madrid 28007, Spain - Author
Hosp Univ Princesa, Serv Endocrinol, Madrid 28006, Spain - Author
Univ Alcala Henares, Hosp Univ Principe Asturias, Serv Endocrinol, Madrid 28805, Spain - Author
Univ Autonoma Madrid, Hosp Univ Princesa, Serv Pathol, Madrid 28006, Spain - Author
Univ Autonoma Madrid, Inst Princesa, Hosp Univ Princesa, Serv Surg & Digest Surg, Madrid 28006, Spain - Author
Univ Autonoma Madrid, Inst Princesa, Immunol & Mol Biol Unit, Madrid 28006, Spain - Author
Univ Complutense Madrid, Hosp Clin San Carlos, Serv Endocrinol, Madrid 28040, Spain - Author
Univ Santiago Compostela, Hosp Clin Univ, Serv Endocrinol, La Coruna 15706, Spain - Author
Univ Santiago Compostela, Hosp Clin Univ, Serv Pathol, La Coruna 15706, Spain - Author
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Abstract

Simple Summary Gastroenteropancreatic 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.

Keywords

biomarkergastroenteropancreatic neuroendocrine tumorsglut-1lat-1Acid transporter 1AssociationBiomarkerCancerGastroenteropancreatic neuroendocrine tumorsGlucose transportersGlut-1GrowthGuidelinesLat-1MetastasisMtorc1Neuroendocrine tumorsPathwayProgression

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cancers due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2020, it was in position 51/242, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 3.27, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-09, the following number of citations:

  • WoS: 7
  • Scopus: 11
  • Europe PMC: 7
  • OpenCitations: 10

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-09:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 20 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

    • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
    • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/695761

    Leadership analysis of institutional authors

    There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (SAMPEDRO NUÑEZ, MIGUEL ANTONIO) and Last Author (MARAZUELA AZPIROZ, MONICA).

    the author responsible for correspondence tasks has been MARAZUELA AZPIROZ, MONICA.