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RET mutation negative MTCs, and endocrine syndrome- proteins including calcitonin and chromogranin A, as well
related MTCs. Exome sequencing of 17 sporadic MTCs as ASCL1 (also important in pulmonary NETs). Notch is
identified the expected mutually exclusive RAS and one of the pathways regulating the production of ASCL1,
RET mutations, but no other commonly occurring driver especially during development. Notch1 expression is absent
mutations. [148] Exome sequencing of MTCs associated in MTC and overexpression of the Notch intracellular
with MEN2A also identified the expected RET mutations, domain decreases proliferation of MTC cell lines,
[55]
but also suggested that low frequency mutations such as consistent with its role as a tumor suppressor. Activation of
those found in EIF4G1 may also play a role in MEN2A- Notch in MTC by pharmaceutical means became possible
associated tumorigenesis by indirectly altering the RET when valproic acid was reported to activate Notch in
pathway. [158] A similar study was undertaken by Smith neuroblastoma cells [169] and subsequent work demonstrated
et al. [159] in MTCs lacking an identifiable RET mutation. that valproic acid increased Notch1 signaling and induced
Interestingly, this group found a recurrent mutation in apoptosis in MTC cells. [170] Using a mouse model system,
the ESR2 gene which encodes the estrogen receptor beta Jaskula-Sztul et al. [171] demonstrated that activation of the
(ER). Estrogen receptor alpha (ER) and ER can form Notch signaling pathway may be a therapeutic strategy for
heterodimers and bind to estrogen response elements MTC. This same group expanded our knowledge of Notch
to regulate gene expression. [160] Alternatively, ER can signaling in MTC by upregulating Notch3 in vitro and in
antagonize the transcriptional activity of ER. [161-163] The vivo via NICD3 and the pharmacological HDAC inhibitor
RET gene contains three ERE sites that were shown to ABA3. They demonstrated that Notch3, like Notch1, can
be actively regulating RET gene expression in vitro. The alter the neuroendocrine phenotype in MTC, resulting
authors propose that this may be a novel mechanism by in decreased proliferation and loss of NET markers. [172]
which the RET gene is regulated in RET mutation-negative Resveratrol treatment of MTC cells suppresses growth,
familial MTC. [159] Heilmann et al. [164] performed genomic induces apoptosis and reduces expression of chromogranin
profiling of MTC cases during the course of clinical A and ASCL1 as a result of upregulation of Notch2. [173] In
care and in addition to the expected RET mutations, similar studies, thiocoraline treatment in vitro increases the
also identified amplifications of CCND1, FGF3, FGF19 expression of Notch1 and Notch2 isoforms, as well as the
and CDKN2A. The authors propose that these may be downstream Notch target genes HES1, HES2 and HEY1,
cooperating driver mutations impacting chemoresistance while expression of HES6 decreased. [174] Taken together,
and disease outcomes. these studies indicate a clear role for Notch signaling in
MTC therapy.
Cancer stem cells have been identified in MTC cell lines
that are strongly positive for the cell surface antigen CONCLUSION
CD133 by immunohistochemistry. [165] Interestingly, cell
lines with the M918T RET mutation produce the highest The role of Notch signaling in NETs remains incompletely
number of CD133 stem-like cells. [165] This population of understood. Further study is required to understand how
+
stem-like cells may also be involved in chemoresistance. this pathway impacts tumorigenesis and chemoresistance
In a study by Kucerova, CD133 cells from MTC cell lines in this diverse tumor group. There is evidence that different
+
were no more chemoresistant than the parent population of Notch isoforms act as tumor suppressors in some NETs
cells. However, once the CD133 cells were implanted in but not others and paralog specific effects are understudied
+
mice as xenografts and treated with 5-fluorouracil (5-FU), and remain unclear. The significant genetic heterogeneity
there emerged a new CD133 stem-like cell population of NETs suggests that individual molecular subtypes must
+
that was resistant to subsequent 5-FU therapy and retained be studied separately to dissect the roles of Notch signaling
these chemoresistant properties in culture. [166] MTCs are components and their potential therapeutic implications.
relatively resistant to the radioactive iodine therapies used
for follicular and poorly differentiated thyroid cancers, Financial support and sponsorship
and one group treated MTC stem cells with all-trans- This work was supported by the Louisiana State University
retinoic acid (ATRA) to sensitize these cells to radioiodine Health Science Center School of Medicine, Department
therapy. The stem cells identified and treated with ATRA of Genetics.
increased their uptake of iodine by 8 fold, suggesting
that ATRA pre-treatment followed by radioactive iodine Conflicts of interest
therapy may be a new treatment modality for MTC. [167] There are no conflicts of interest.
Finally, co-expression of CD133 and CD44 in MTC by
immunohistochemistry was correlated with decreased REFERENCES
overall survival in a cohort of 51 MTC patients, compared
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immunity. Front Oncol 2014;4:345.
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markers for overall survival. [168] in development and disease. Cell Mol Life Sci 2014;71:3553-67.
3. Jin S, Mutvei AP, Chivukula IV, Andersson ER, Ramskold D,
At the molecular level, MTC cells express a variety of Sandberg R, Lee KL, Kronqvist P, Mamaeva V, Ostling P, Mpindi
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