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and the role of cancer stem cells in NET pathogenesis, is independent of CSL and can be ligand-dependent or
chemoresistance and recurrence. independent. [1,20] Compared to canonical Notch signaling,
knowledge of non-canonical Notch mechanisms is
NOTCH SIGNALING limited, with the majority of studies performed in cancer
and immune system cells. Non-canonical Notch
[1]
The Notch signaling pathway is an evolutionarily pathways present an interesting new avenue of study and
conserved, critical component of basic cellular may reveal new targets for therapeutic intervention in the
processes such as proliferation, stem cell maintenance, translational setting.
and differentiation during both embryonic and adult
development. The canonical Notch signaling pathway has One mechanism of non-canonical Notch signaling occurs
been well-studied and typically depends on the binding of through the Wnt/β-catenin pathway in cancer and the
a Notch receptor to its ligand residing on a neighboring immune system. The Wnt/-catenin pathway regulates
cell. This ligand binding promotes the separation of cell pluripotency and cell fate decisions, and aberrant
the extracellular subunit from the transmembrane functions or mutations in β-catenin have been associated
subunit, which is followed by cleavage of the receptor’s with a number of cancers and other human diseases. Non-
transmembrane subunit by ADAM metalloproteases canonical Notch signaling can result in an antagonistic
(primarily ADAM-10) and gamma secretase. The latter interaction between Notch signaling and Wnt/β-
cleavage releases the active form of Notch, the Notch catenin [2,20,21] that disrupts the regulation of developmental
intracellular domain (NICD). The NICD then translocates and disease processes. This results in an inverse
[20]
into the nucleus and binds to the transcription factor relationship between elevated levels of membrane-bound
CSL (CBF-1/Suppressor of Hairless/LAG1), also known Notch and lower levels of active β-catenin leading to
[20]
as RBP-Jk, to control expression of Notch-regulated negative regulation of Wnt signaling. One example of
[4]
genes. [15-18] Ligand-independent activation of Notch this crosstalk is the loss of Notch1 in the epidermis of mice,
cleavage has been reported in some contexts, notably which results in activated Wnt/-catenin signaling and the
breast cancer stem cells, where it is mediated by activation formation of hyperplasia and cancer -- both of which can
of ADAM-17 via the Sphingosine 1-phosphate pathway. [19] be reversed by the introduction of exogenous NICD. [22]

Different species contain different numbers of Notch Non-canonical Notch signaling is also involved in the
isoforms. Drosophila contains one Notch receptor, C. activation and proliferation of CD4 T cells in the immune
+
elegans has two redundant receptors, and mammals contain system as well as in the tumor-promoting effects of
four Notch receptors, Notch1-4. Notch receptors contain interleukin-6 (IL-6). [1,23] These events rely on NF-κB and
an extracellular domain that includes multiple epidermal demonstrate crosstalk with other cellular pathways in
growth factor (EGF)-like repeats in varying numbers the absence of canonical Notch signaling. Studies have
that are involved in ligand binding. The intracellular demonstrated that even in the absence of CSL, CD4
+
portion of Notch transmits cellular signals and contains T-cell activation and proliferation through NF-κB requires
an RBP-Jκ Association Module (RAM) domain, a nuclear NICD playing a major role in the signature CBM complex
localization signal (NLS), a seven ankyrin repeat (ANK) (CARMA1, MALT1 and BCL10). The NICD can also
[24]
domain and a transactivation domain that contains activate a non-canonical signaling cascade via mTORC2
conserved proline/glutamic acid/serine/threonine-rich and Akt as a means of transmitting extracellular nutrient
(PEST) motifs. For a comprehensive review of known sensing cues to promote cell survival. [5,25] Notch signaling,
Notch ligands, see. In mammals, Notch ligands include both canonical and non-canonical, is regulated by a
[17]
Delta-like1 (DLL1), Delta-like3 (DLL3) and Delta-like4 myriad of known and unknown binding partners as well as
(DLL4), which are homologous to Drosophila Delta, posttranslational modifications. Comprehensive reviews
along with Jagged1 (JAG1) and Jagged2 (JAG2), which of Notch signaling are available. [18,26,27]
have homology to Drosophila Serrate. Notch ligands have
multiple EGF-like repeats in their extracellular domains NETs - ENTEROPANCREATIC
and all contain an N-terminal DSL (Delta/Serrate/LAG2)
motif that, along with the first two EGF-like repeats is The annual incidence of enteropancreatic NETs is
required for ligand-receptor interaction. Jagged ligands 2-5/100,000 patients in the United States and recent studies
contain almost twice the number of EGF repeats as well suggest that this incidence will continue to rise in the
as an additional cysteine rich region compared to DLL coming years. [21,28-30] Overall survival (OS) for metastatic
ligands. The intracellular portion of all Notch ligands pancreatic and small bowel NETs is 24 and 56 months,
[29]
lacks major homology with the exception that some, but respectively. Enteropancreatic NETs, or NETs that form
not all, ligands contain multiple lysine residues and a in the pancreas or the gut (also called carcinoids), can be
C-terminal PDZ (PSD-95/Dlg/ZO-1) domain. categorized as functional or non-functional depending on
their level of hormone release. Pancreatic NETs can hyper
In addition to the well-studied canonical signaling, Notch secrete insulin (insulinoma), glucagon (glucagonoma),
signaling can also occur in a non-canonical fashion that somatostatin (somatostatinoma), pancreatic polypeptide
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦