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very small numbers of cells. Cancer stem cells are often degradation of hASH1. Transient overexpression of
[57]
chemoresistant, mediate tumor recurrence, and recruit the NICD in BON1 cells resulted in increased proliferation
host immune system through a variety of mechanisms to and dose-dependent increases in Hes1. In contrast,
support tumor cell growth and metastasis. [45] immunohistochemistry for Notch1, Hes1, Hey1, pIGF1R
and FGF2 antibodies on a tissue microarray of 120 well
Cancer stem cells have been identified in gastrointestinal differentiated NETs arising from the pancreas (n = 74),
[50]
and pancreatic NETs. In gastrointestinal NETs, a ileum (n = 31) and rectum (n = 15), demonstrated elevated
[51]
population of stem cells was identified based on ALDH Notch1 expression in 100% rectal, 34% of pancreatic, and
positivity which is required for chemoresistance and 0% of ileal NETs, and Hes1 expression in 64% of rectal,
enhances self-renewal. ALDH+ cells exhibit anchorage- 10% of pancreatic and 0% of ileal NETs, exhibiting
[50]
[58]
independent growth and have elevated expression of Src, significant variability in Notch1 signaling across different
Erk, Akt and mTOR. Because therapies directed towards tissue types. There is limited information on other Notch
the Akt/mTOR pathway are already clinically validated in receptors or the ligands involved in Notch signaling in
NETs, the investigators focused on Src and treated mouse NETs and a comprehensive analysis of Notch expression
xenografts with anti-Src siRNA. This treatment resulted in patterns across all enteropancreatic NET subtypes is
a 91% decrease in tumor mass and suggested an additional required to fully understand the variability and potentially
treatment avenue for gastrointestinal NETs. In pancreatic redundant functions of Notch receptors and ligands.
[50]
NETs, stem cells have been isolated that co-express the
cell-surface protein CD90 and aldehyde dehydrogenase The ability of Notch to behave as an oncogene or tumor
A1 (ALDHA1), as well as CD47 which serves as a flag to suppressor depending on cellular context is driven in part
evade the immune system. These stem-like cells form by the availability of coactivators and corepressors. CSL
[51]
tumors in mice and the treatment of tumor-bearing mice coactivators such as MAML, SKIP and p300 are well
with anti-CD47 antibody therapy inhibits tumor growth, known to activate transcription of Notch target genes by
prevents metastasis and prolongs survival. Combination binding to NICD. Conversely, in the absence of NICD,
therapy with anti-CD47 and anti-EGFR (expressed by corepressors also regulate transcription in specific ways
the majority of pancreatic NETs) in the preclinical setting and canonical Notch corepressors include SMRT,
[59]
demonstrated improved efficacy over anti-CD47 antibody SIRT and LSD1 (histone lysine demethylase), among
[61]
[60]
therapy alone and supports the notion that treatment of others (reviewed in ). Epigenetic regulation by Notch
[62]
[51]
human pancreatic NETs with stem cell specific antigens activator and repressor complexes containing histone
will yield clinically significant results. acetyltransferases, histone demethyltransferases, histone
methyltransferases, etc. actively remodel the chromatin at
NETs in general remain significantly understudied with Notch-responsive target genes and provide an additional
respect to molecular mechanisms of pathogenesis, and layer of reversible regulation. Chromatin sites accessible
[63]
particularly Notch signaling. Mechanistically, Notch may to Notch NICDs are also influenced by transcriptional
contribute to carcinogenesis by inhibiting differentiation, regulators that can act as cofactors or inhibitors. [64-66]
promoting cellular proliferation and/or inhibiting A recent report by Liefke et al. demonstrates that the
[63]
apoptosis, yet few studies have comprehensively examined histone demethylase KDM5A/RBP2 is a key component
these endpoints with respect to the four Notch receptors of the CSL repressor complex. Data from our laboratory
and their ligands in NETs. The available studies suggest demonstrates that RBP2 is upregulated in gastrointestinal
a tumor suppressive function for Notch1 in cells derived NETs and in liver metastases from primary NET tumors,
from the neuroendocrine lineage. This is consistent with suggesting that RBP2 may be actively repressing canonical
role of Notch in Drosophila neurogenesis, where Notch Notch activity (Crabtree, et al. 2016 Oncogenesis in press).
restricts differentiation towards the neuronal lineage. The
loss of Notch in Drosophila embryos results in uncontrolled NETs - PULMONARY
ectodermal differentiation down the neuronal lineage. [52,53]
It is plausible that loss of Notch signaling would allow Pulmonary NETs are an equally diverse set of NETs
NET cells to acquire or maintain a partially differentiated that fall on a continuum from well-differentiated typical
neuroendocrine phenotype while retaining the ability to carcinoid (TC), to less differentiated atypical carcinoid
proliferate. For example, recent studies [11,12,54-57] report that (AC), to highly malignant, poorly differentiated small cell
Notch1 signaling is minimal or absent in gut carcinoids, lung carcinoma (SCLC) and large cell neuroendocrine
medullary thyroid carcinoma (MTC) and pulmonary carcinoma (LCNECs). Features distinguishing these
[67]
typical and atypical carcinoids. Yet these same cancers groups include size, with TC and AC defined as ≥ 0.5 cm,
express high levels of human achaete-scute homolog 1 and histologic characteristics such as organoid growth
(hASH1), a basic helix loop helix transcription factor that patterns with uniform cytologic features. These tumors
is regulated by Notch signaling. The aberrant expression contain a moderate amount of eosinophilic cytoplasm
of hASH1 and the arrest of NET cells at an early stage of and nuclei containing finely granulated chromatin,
differentiation may be due to decreased Notch1-activated which is coarser in AC than in TC. Prominent nucleoli
expression of Hes1 and Hes5 which both facilitate are also present in AC, but not in TC. New 2015 WHO
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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 17, 2016 ¦