Multilayered heterogeneity as an intrinsic hallmark of neuroendocrine tumors

  • Sergio Pedraza-Arévalo
  • Manuel D. Gahete
  • Emilia Alors-Pérez
  • Raúl M. LuqueEmail author
  • Justo P. CastañoEmail author


Neuroendocrine tumors (NETs) comprise a complex and highly heterogeneous group of neoplasms that can arise all over the body, originating from neuroendocrine cells. NETs are characterized by a general lack of symptoms until they are in advanced phase, and early biomarkers are not as available and useful as required. Heterogeneity is an intrinsic, pivotal feature of NETs that derives from diverse causes and ultimately shapes tumor fate. The different layers that conform NET heterogeneity include a wide range of distinct characteristics, from the mere location of the tumor to its clinical and functional features, and from its cellular properties, to the core signaling and (epi)genetic components defining the molecular signature of the tumor. The importance of this heterogeneity resides in that it translates into a high variability among tumors and, hence, patients, which hinders a more precise diagnosis and prognosis and more efficacious treatment of these diseases. In this review, we highlight the significance of this heterogeneity as an intrinsic hallmark of NETs, its repercussion on clinical approaches and tumor management, and some of the possible factors associated to such heterogeneity, including epigenetic and genetic elements, post-transcriptional regulation, or splicing alterations. Notwithstanding, heterogeneity can also represent a valuable and actionable feature, towards improving medical approaches based on personalized medicine. We conclude that NETs can no longer be viewed as a single disease entity and that their diagnosis, prognosis and treatment must reflect and incorporate this heterogeneity.


Neuroendocrine tumors Heterogeneity Hallmark Cancer Carcinoid Complexity 


Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare in this work.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Maimonides Institute for Biomedical Research of Cordoba (IMIBIC)CórdobaSpain
  2. 2.Department of Cell Biology, Physiology, and ImmunologyUniversidad de CórdobaCórdobaSpain
  3. 3.Reina Sofia University HospitalCórdobaSpain
  4. 4.CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn)CórdobaSpain
  5. 5.Agrifood Campus of International Excellence (ceiA3)CórdobaSpain

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