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Topic: Neuroendocrine Tumors

Neuroendocrine tumors: current therapies, notch signaling, and cancer
stem cells

Judy S. Crabtree, Lucio Miele
Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Correspondence to: Dr. Judy S. Crabtree, Department of Genetics, Louisiana State University Health Sciences Center, 533 Bolivar Street, New
Orleans, LA 70112, USA. E-mail: jcrabt@lsuhsc.edu

A B S T R AC T
Neuroendocrine tumors (NETs) encompass a broad spectrum of malignancies all derived from neuroendocrine cell lineage,
affecting many different organs including the gastrointestinal (GI) tract, the endocrine pancreas, the thyroid, the skin and the
respiratory tract. These tumors as a group are very heterogeneous, with varying characteristics attributed to each tissue of
origin and tumor subtype. The pathogenesis of the different subtypes of NETs is not fully understood, but recent studies suggest
the Notch signaling pathway may be dysregulated in these tumors either by under or overexpression of Notch receptors and/or
ligands, or by disruption of pathway functionality through other means. Notch receptors can function as tumor suppressors in
some cellular contexts and oncogenes in others which may, in part, account for the wide range of phenotypes present in NETs.
Cancer stem cells are present in these tumors and may be responsible for the high rate of chemotherapy resistance, recurrence
and metastasis. The heterogeneity of NETs suggests that to fully understand the role of Notch signaling and the therapeutic
implications thereof, a comprehensive and systematic analysis of Notch expression and function across all NET subtypes is
required. Here we outline the current knowledge base with respect to current therapies and Notch signaling in neuroendocrine
tumors of the lung, skin, thyroid, GI tract and endocrine pancreas.

Key words: Neuroendocrine tumor; Notch; small cell lung carcinoma; medullary thyroid carcinoma; merkel cell carcinoma;
pancreatic NET; carcinoid

INTRODUCTION more and more evident. Notch signaling is classified into
two broad categories: 1) canonical signaling, wherein
Neuroendocrine tumors (NETs) are a heterogeneous Notch receptors regulate transcription through CSL (CBF-
group of neoplasms that arise from the neuroendocrine 1/Suppressor of Hairless/LAG-1), also known as RBP-
cells of the gastrointestinal (GI) tract, endocrine pancreas, Jk, and can play an oncogenic or tumor suppressive role
thyroid, skin, lung, adrenal gland and other tissues. These depending on context, or 2) non-canonical, which functions
tumors are typically slow-growing, yet pose a significant through interplay with other signaling networks including
threat due to high metastatic potential. In many cases, phosphatidylinositol 3’ kinase (PI3K)/Akt, mTOR, NF-
patients initially present with advanced metastatic disease kB and beta-catenin. [1-6] In NETs, interactions with these
resulting in poor outcomes and low 5-year survival rates. pathways as well as complexes between canonical Notch
An understanding of the mechanism(s) of tumorigenesis target hairy enhancer of split 1 (Hes1) and achaete-schute
and metastasis is required for target identification and new complex-like 1 (ASCL-1) have been reported. [7-14] Many
therapeutic development, since many NET subtypes have of these pathways can be pharmacologically modulated
no curative options beyond surgical resection. for translational research and eventually for experimental
therapy of NETs, once the role of Notch signaling in
In recent years, studies have suggested that the Notch these tumors is more clearly elucidated. Here we review
signaling pathway may be involved in the pathogenesis the current state of NET therapies, the role of canonical
of NETs. Notch signaling has been studied for many and non-canonical Notch signaling in these tumor types,
years in the context of cancer and as these pathways are
dissected, the complexity of Notch signaling becomes This is an open access article distributed under the terms of the Creative
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How to cite this article: Crabtree JS, Miele L. Neuroendocrine
tumors: current therapies, notch signaling, and cancer stem cells. J
DOI: Cancer Metasta Treat 2016;2:279-93.
10.20517/2394-4722.2016.30
Received: 02-06-2016; Accepted: 01-08-2016.

©2016 Journal of Cancer Metastasis and Treatment ¦ Published by OAE Publishing Inc. 279