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com
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doi:10.3748/wjg.v20.i9.2247
World J Gastroenterol 2014 March 7; 20(9): 2247-2254
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
2014 Baishideng Publishing Group Co., Limited. All rights reserved.
Embryonic stem cell factors and pancreatic cancer
Marta Herreros-Villanueva, Luis Bujanda,

Daniel D Billadeau, Jin-San Zhang
Marta Herreros-Villanueva, Daniel D Billadeau, Jin-San
Zhang, Division of Oncology Research, Schulze Center for
Novel Therapeutics, Mayo Clinic College of Medicine, Roches-
ter, MN 55905, United States
Marta Herreros-Villanueva, Luis Bujanda, Department of Gas-
troenterology, Hospital Donostia/Instituto Biodonostia, Centro de
Investigacin Biomdica en Red de Enfermedades Hepticas y
Digestivas (CIBERehd), Universidad del Pas Vasco UPV/EHU,
20014 San Sebastin, Spain
Jin-San Zhang, School of Pharmaceutical Sciences, Key Labo-
ratory of Biotechnology and Pharmaceutical Engineering, Wen-
zhou Medical University, Wenzhou 325000, Zhejiang Province,
China
Author contributions: Zhang JS selected the topic; Herreros-
Villanueva M and Zhang JS designed, wrote and edited the
manuscrip; Bujanda L and Billadeau DD provided partial fund-
ing; all authors approved the manuscript.
Supported by Universidad del Pais Vasco, Instituto Biodonostia,
San Sebastian, and CIBERehd (red de enfermedades hepaticas y
digestivas); American Cancer Society institutional award; Mayo
Clinic Pancreatic Cancer SPORE, No.CA102701
Correspondence to: Jin-San Zhang, MD, PhD, Division of
Oncology Research, Schulze Center for Novel Therapeutics,
Mayo Clinic College of Medicine, Rochester, MN 55905,
United States. [email protected]
Telephone: +1-507-2669310 Fax: +1-507-2665146
Received: October 28, 2013 Revised: December 15, 2013
Accepted: January 14, 2014
Published online: March 7, 2014
Abstract
Pancreatic ductal adenocarcinoma (PDAC), the most
common type of pancreatic tumor, is a highly aggres-
sive human cancer with the lowest five-year survival
rate of any human maligancy primarily due to its early-
metastasis and lack of response to chemotherapy and
radiation. Recent research suggests that PDAC cells
comprise a hierarchy of tumor cells that develop around
a population of cancer stem cells (CSCs), a small and
distinct population of cancer cells that mediates tumor-
egenesis, metastasis and resistance to standard treat-
ments. Thus, CSCs could be a target for more effective
TOPIC HIGHLIGHT
treatment options. Interestingly, pancreatic CSCs are
subject to regulation by some of key embryonic stem
cell (ESC) transctiption factors abberently expressed in
PDAC, such as SOX2, OCT4 and NANOG. ESC transcrip-
tion factors are important DNA-binding proteins present
in both embryonic and adult somatic cells. The critical
role of these factors in reprogramming processes makes
them essential not only for embryonic development but
also tumorigenesis. Here we provide an overview of
stem cell transcription factors, particularly SOX2, OCT4,
and NANOG, on their expression and function in pan-
creatic cancer. In contrast to embryonic stem cells, in
which OCT4 and SOX2 are tightly regulated and physi-
cally interact to regulate a wide spectrum of target
genes, de novo SOX2 expression alone in pancreatic
cancer cells is sufficient to promote self-renewal, de-
differentiation and imparting stemness characteristics
via impacting specific cell cycle regulatory genes and
epithelial-mesnechymal transtion driver genes. Thus,
targeting ESC factors, particularly SOX2, could be a
worthy strategy for pancreatic cancer therapy.
2014 Baishideng Publishing Group Co., Limited. All rights
reserved.
Key words: Embryonic stem cells; NANOG; SOX2;
OCT4; Pluripotency; Pancreatic cancer; Cancer stem
cells
Core tip: Pancreatic ductal adenocarcinoma (PDAC) is
one of the most lethal human cancer due to its early
metastasis and lack of response to chemoradiotherapy.
Pancreatic cancer stem cells (CSCs) are implicated in
tumorigenesis and metastasis as well as therapy resis-
tance, therefore represent a potential target for effec-
tive therapeutic options. Recent publications including
our own research demonstrate that key embryonic
stem cell (ESC) factors, such as OCT4, NANOG and
SOX2, are abbrently expressed in PDAC and contrib-
ute to pancreatic CSC-like characteristics, such as self-
renewal and de-differentiation. This review aims to
summarize our current knowledge on the role of ESC
pluripotent stem cells (iPSCs), which are artifcially engi-
neered from a non-pluripotent cell, such as via somatic
cell nuclear transfer or reprograming with gene transfer.
The generation of iPSCs represents a milestone achieve-
ment in SC research, which not only breaks the dogma
that somatic cell differentiation is an irreversible process,
but also makes possible a new approach for regenera-
tive medicine without controversial use of embryos.
The fourth SC type is CSCs, also referred to as cancer
initiating cells (CICs), which are defined as those cells
within a tumor that can self-renew, produce differentiated
progeny, and drive tumorigenesis. The ability of cancer
cells to form nonadherent spheroids in vitro culture is
frequently used as a surrogate of stemness. Unlike ESCs,
CSCs are highly heterogenous with great variation among
the markers for each tumor type.
ESCs AND ESC TRANSCRIPTION
FACTORS
ESCs are derived from the inner cell mass (ICM) of the
preimplantation mammalian embryo and can be main-
tained indefinitely in culture
[13]
. By definition, ESCs are
pluripotent. They are able to give rise to all somatic and
the three germ cell lineages of the developing embryo.
Pluripotency is maintained through self-renewal, which
allows ESCs to duplicate themselves without losing the
ability to differentiate. This can be achieved via both sym-
metric and asymmetric cell divisions
[14]
.
Over the last decade, there has been accumulating
evidence indicating that the maintenance of pluripotency
in ESCs is governed by core genetic and epigenetic regu-
lators, which allow self-renewal and prevents specific
differentiation pathways. Recent progress on the mo-
lecular mechanism(s) governing stem cells pluripotency
has provided critical insights into the role of nine core
transcription factors OCT4 (POU5F1), NANOG, SOX2,
Dppa4, Dppa5, Sall4, Utf1, Rex2, and Rif1 in maintain-
ing mouse cells in the undifferentiated stage
[15-18]
. Among
these genes, OCT4, NANOG, and SOX2, referred to as
pluripotency genes, are highly expressed in the ICM. The
perfect balance of these proteins maintains pluripotency
and self-renew in ESC during the frst days of embryonic
development
[18]
. Broadly, the pluripotency genes have
been shown to be common to all SC types (Figure 1). In
contrast to OCT4, NANOG and SOX2, c-MYC, an im-
portant oncogene as well as a reprogramming factor for
pluripotency
[17]
, is highly heterogeneous in cells from the
ICM. However, it is not always considered a pluripotency
gene in ESCs. The activity of these three core pluripo-
tency genes regulates and coordinates the expression of a
second set of core genes, which include transcription fac-
tos, cell surface markers, ABC transporters, and enzymes.
Together, these proteins orchestrate the specific stem
cells properties
[19]
.
SOX2 and OCT4 form a protein complex in the nu-
cleus of ESCs. This complex is auto-regulated in a loop
2248 March 7, 2014|Volume 20|Issue 9| WJG|www.wjgnet.com
Herreros-Villanueva M et al . Stem cell factors and pancreatic cancer
factors particulary SOX2 in regulating pancreatic CSC-
like feature and implication for therapy.
Herreros-Villanueva M, Bujanda L, Billadeau DD, Zhang JS.
Embryonic stem cell factors and pancreatic cancer. World J
Gastroenterol 2014; 20(9): 2247-2254 Available from: URL:
http://www.wjgnet.com/1007-9327/full/v20/i9/2247.htm DOI:
http://dx.doi.org/10.3748/wjg.v20.i9.2247
INTRODUCTION
Pancreatic cancer is the fourth leading cause of cancer
death in men and women in the United States. In 2012
alone, an estimated 43920 adults in the United States
were diagnosed with pancreatic cancer and 37390 deaths
from this disease ocurred
[1]
. About 280000 new cases of
pancreatic cancer were recorded in 2008 worldwide. Pan-
creatic ductal adenocarcinoma (PDAC), the most com-
mon type of pancreatic cancer, is also the most lethal
among the human solid tumors with a 5-year survival
rate of less than 5 percent
[2]
. The main reasons for this
outcome include lack of early detection, invasive behav-
ior and intrinsic resistance to most chemo-/radio- and
immuno-therapy strategies
[3,4]
. Recently, several studies
have identified PDAC cancer stem cells (CSCs), which
are highly tumorigenic and have the capacity to not only
self-renew, but also generate differentiated progeny
[3,5-7]
.
Pancreatic CSCs are also resistant to chemotherapies
commonly used to treat patients with PDAC
[8-10]
. Thus,
studies identifying key determinants in pancreatic cancer
and pancreatic CSCs can provide both biomarkers of
PDAC aggressiveness and potentially optimal targets to
overcome chemoresistance (Table 1). Here we review
how embryonic stem factors contributes to the agres-
siveness of this disease and the potential for targeted
therapy.
STEM CELL DEFINITION AND TYPES
Stem cells (SCs) are traditionally defined as cells that
can both self-renew and generate a progeny that are
capable of following more than a single differentiation
pathway
[11]
. Currently, four types of SCs have been de-
scribed
[12]
. The first two are physiologically present at
different stages of life, namely, the embryonic stem cells
(ESCs) and the somatic or adult stem cells (ASCs). The
ESCs are the best studied SCs and knowledge derived
from ESCs research has guided the investigations of oth-
er types of SCs. ASCs are postnatal derivatives of ESCs
located throughout the body. ASCs have been shown to
retain co-expression of at least three of the core tran-
scription factors characteristic of ESCs (OCT4, KLF4,
and SOX2). Similar to ESCs, the presence of a balanced
network of core stem markers, rather than the overt ex-
pression of a single factor, contributes to maintainenance
of ASC characteristics. The third SC type is induced
that, transcriptionally, also induces the expresion of plu-
ripotency genes (most importantly NANOG), cell cycle,
apoptosis, DNA repair, chromatin structure genes, and
genes regulating endoderm, mesoderm, and ectoderm
differentiation. Thus, tight control of all these genes
may allow ICM cells to exit from their inherent develop-
mental program, as they acquire the ability to self-renew,
while retaining pluripotency as ESCs
[20]
. Finally, when
the expression of these pluripotency genes decreases in
a properly regulated way, an induction in the expression
of early differentiation markers occurs. These markers
include ectoderm markers (Pax6, Otx1, Neurod1, Nes,
Lhx5, and Hoxb1), mesoderm markers (Tbx2, T, Nkx2-5,
Myod1, Myf5, Mesdc1, Mesdc2, Kdr, Isl1, Hand1 and Eomes),
endoderm markers (Onecut1, Gata4, Gata5, and Gata6),
and extraembryonic markers (Cdx2 and Tpbpa).
KEY ESC FACTORS IN IPSCs
iPSCs were first derived by the transduction of mouse
and human fbroblasts through integrating viruses carry-
ing four transcription factors: OCT4, SOX2, MYC and
Krupple-like factor 4 (KLF4)
[21]
, also referred as the Ya-
manaka factors. Takhashi and Yamanaka
[21]
broke a dog-
ma in developmental biology by showing that mammalian
somatic cell differentiation is a reversible process
[17,21]
. By
transfecting human somatic cells with the four Yamanaka
factors, they were able to revert the differentiated cells to
an embryonic-like state. Because these newly generated
cells showed the morphology, pluripotency, and capac-
ity to form teratomas similar to ESCs, they named these
cells iPSCs. Later, Yu et al
[22]
further demonstrated that
the combination of OCT4, NANOG, SOX2 and Lin28,
also called Thomson Factors, was able to produce iPSCs.
Both, Yamanaka and Thomson Factors are Reprogram-
ming Factors as Reprogramming is the process that con-
verts differentiated cells back to pluripotent cells, namely
the reversal of differentiation.
Recently, new methods have been developed to repro-
gram human somatic cells with or without MYC
[22,23]
and
to combine only some of the reprogramming transcrip-
tion factors with chemical inhibitors
[24-26]
. However, the
fact remains that OCT4, SOX2, MYC, and KLF4 reside
at the heart of the reprogramming process. Given that
the transcription factors in this network not only associ-
ate with one another, but also associate with many of
the same proteins in the network, there is a high degree
of interdependence between these transcription factors.
Thus, it is not surprising that the levels of SOX2 and
OCT4 need to be controlled carefully for optimal pro-
duction of iPSC, or that small changes in the levels of
these master regulators can lead to dramatically altered
cell fates. However, it remains to be determined how
2249 March 7, 2014|Volume 20|Issue 9| WJG|www.wjgnet.com
Table 1 Biological role and clinical implications for embryonic stem cell factors in pancreatic cancer
Gene Biological role/behaviour PDAC implications Ref.
OCT4 Overexpressed in 69% of PDAC. Pro-oncogenic role Correlation with N1/M1 status and indicative of worse
prognosis
Polvani et al
[47]
, 2013
Overexpressed in 48.8% of PDAC. Induces cell
proliferation, migration and invasion
Contribution to metastasis and drug resistance Lu et al
[50]
, 2013
Overexpressed in human cell lines Multidrug resistance and metastasis Wang et al
[52]
, 2013
Induction of tumorigenic capacity Chemo-resistance Wang et al
[53]
, 2013
Overexpressed in 79.2% metaplastic ducts Early carcinogenesis and worse prognosis Wen et al
[49]
, 2010
SOX2 Overexpressed in poorly differentiated human tumors Correlation to aggressiveness Sanada et al
[54]
, 2006
Ectopic expression in 19.3% of PDAC. Promotes cancer
cell proliferation/dedifferentiation
Rapid tumor progression and poor differentiation Herreros-Villanueva et al
[38]
,
2013
Induction of tumorigenic capacity Chemo-resistance Wang et al
[53]
, 2013
NANOG Overexpressed in 53.5% of PDAC. Induces
proliferation, migration and invasion
Associated with eraly stage carcinogenesis and worse
overall survival
Lu et al
[50]
, 2013
Overexpressed in cells capable of initiating spheres Resistance to 5-FU treatment Lonardo et al
[68]
, 2013
Overexpressed in pancreatic tumors Contribution to carcinogenesis and correlates to worse
prognosis
Wen et al
[49]
, 2010
PDAC: Pancreatic ductal adenocarcinoma.
ASCs ESCs
iPSCs CSCs
OCT4
SOX2
NANOG
Figure 1 Overlapping expression of SOX2, NANOG, and OCT4 in all four
types of stem cells: embryonic stem cells, adult stem cells, induced plu-
ripotent stem cells, and cancer stem cells. ASCs: Adult stem cells; ESCs:
Embryonic stem cells; iPSCs: Induced pluripotent stem cells; CSCs: Cancer
stem cells.
Herreros-Villanueva M et al . Stem cell factors and pancreatic cancer
2250 March 7, 2014|Volume 20|Issue 9| WJG|www.wjgnet.com
to tumor transformation, tumorigenicity, tumor metas-
tasis, and even distant recurrence after chemoradiothera-
py
[42]
. It is well known that these transcription factors are
more frequently overexpressed in poorly differentiated
tumors (compared to well differentiated tumors) and, in
theory, that the expression level of the pluripotent tran-
scription factors should decrease with the differentiation
of cells
[43]
. In this regard, how these genes contribute to
specific CSC properties has not been fully elucidated.
Based on data obtained from iPSCs, several mechanisms
have been proposed to explain the properties that these
transcription factors could be imparting on CSCs. For ex-
ample, once these transcription factors are overexpressed,
they might activate several genes whose promoters are
accessible to them. These first responders must then
engage the epigenetic machinery to remodel the chroma-
tin through histone modifcation and DNA methylation.
In this process, genes critical for pluripotency must be
switched on, while genes responsible for differentiation
must be turned off and kept off
[44]
. From this data, it is
clear that OCT4, NANOG and SOX2 are master regula-
tors, which together drive the transition from a somatic
cell to either a CSC or iPSC (Figure 2).
ESC FACTORS AND PANCREATIC
CANCER
As mentioned above, CSCs have also been described
in PDAC (Table 1). Originally Li et al
[6]
identified hu-
man pancreatic CSCs as CD44
+
/CD24
+
/ESA
+
. A few
months later, Hermann et al
[7]
showed that CD133 and
CXCR4 are also expressed in cells with CSC properties.
In addition, some other markers such as c-Met
[5]
and al-
dehyde dehydrogenase 1 activity (ALDH1)
[45]
have been
demonstrated in pancreatic CSCs. Recently, some reports
describe the presence of a side population (SP) of cells
in pancreatic cancer, a chemoresistant population of
cells that could be enriched in CSCs. Additionally, this
data indicates that SP cells express pancreatic CSC mark-
ers (CXCR4, CD133) and multidrug resistance genes
(ABCB1), associating these cells with candidate therapeu-
tic targets and potential prognostic value
[46]
.
The regulation and characterization of CSCs in vari-
ous types of human cancer, in which SOX2, OCT4 and
NANOG are important players, is currently a hot topic.
However, the number of specifc publications analyzing
their role in pancreatic cancer is very limited. In particu-
lar, a literature search on PUBMED database using the
terms OCT4, NANOG and SOX2 together with
pancreatic cancer, showed 24, 27, and 20 published
articles, respectively. Furthermore, only a few of these
articles discuss these factors in the context of CSCs
(Table 1). Polvani et al
[47]
found that OCT4 is expressed
in 69% of PDAC and that this expression correlates with
N1/M1 status and clinical stage, being an independent
prognostic factor for worst outcomes. In agreement with
several breast cancer publications
[48]
, patients with OCT4
+

PDAC have a shorter survival, suggesting this ESC factor
their levels affect the molecular effciency of reprogram-
ming. Given the strict requirement for SOX2 and OCT4
during development, their key roles in ESC differentia-
tion, and the pronounced differences in reprogramming
when their levels are not optimized, additional efforts
should be made to determine why small changes in the
levels of these two master regulators alters the behavior
of pluripotent stem cells.
ESC FACTORS AND CSCs
Although initially discovered in hematopoietic malignan-
cies, such as acute myelogenous leukemia and chronic
myelogenous leukemia
[27,28]
, CSCs were later described
in various solid tumors, including glioblastoma
[29]
, mela-
nom
[30]
, prostate
[31]
, colon
[32]
head and neck squamous cell
carcinoma
[33]
, breast
[34]
, ovarian
[35]
, bladder
[36]
, lung
[37]
and
pancreatic cancer
[6,7,38,39]
. In these malignancies, a small
population of CSCs can self-renew and differentiate
into all of the other cell types forming the bulk tumoral
population. However, the bulk of tumor cells lack the
ability to differentiate into other subpopulations of can-
cer cells and thus possess limited self-renewal capacity. In
addition, it has been shown that CSCs have tumor initia-
tion capacity, forming xenograph tumors in mice and are
radio- and chemo-resistant, contributing to lack of thera-
peutic response in patients
[39]
.
Although several proteins have been proposed as
CSC markers, there is great variation between tumor
types
[40,41]
. This variation might be the result of the lack
of standardized techniques to obtain and analyze CSCs,
as well as the intrinsic plasticity of these cells
[40]
. Since
CSCs express many genes in common with early ESCs,
primarily OCT4, NANOG, and SOX2, the picture that
emerged was that these transcription factors could also
work together as part of a highly integrated network to
regulate pluripotency and self-renewal in tumors. Nev-
ertheless, the heterogeneity of tumors and the plasticity
that characterize CSCs render the expression pattern of
these transcription factors highly heterogeneous in differ-
ent tumors and even within the same tumor.
Several publications show that overexpression of
OCT4, SOX2 and NANOG, together or separately, led
p27
p21
Cyclin D3
CDK6
Slug
Snail
Twist
SOX2
Figure 2 Diagram depicting the molecular mechanism underlying SOX2
expression-induced self-renewal and pluripotency in pancreatic cancer
stem cells.
Herreros-Villanueva M et al . Stem cell factors and pancreatic cancer
2251 March 7, 2014|Volume 20|Issue 9| WJG|www.wjgnet.com
as a marker of poor prognosis. Importantly, high levels
of OCT4 and NANOG in human pancreatic cancer
tissues were found to be associated with early stages of
carcinogenesis
[49]
and correlate with worse prognosis
[50]
.
Additionally OCT4 seems to contribute to multidrug-
resistance and metastasis
[51,52]
. Wang et al
[53]
recently dem-
onstrated that SP cells positive for NANOG, OCT4 and
SOX2 possessed aggressive growth, invasion, migration
and drug-resistance properties.
To date, very little is known regarding how OCT4
and NANOG contribute to pancreatic CSC properties
at the molecular level. Interestingly, recent studies sug-
gest that SOX2 is aberrantly expressed in a significant
fraction of pancreatic tumors. Initially, Sanada et al
[54]
ana-
lyzed 14 cases of human PDAC immunohistochemically,
and observed weak expression of SOX2 in pancreatic
intraepithelial neoplasia (PanIN-3) lesions. They also ob-
served relatively high and frequent expression in invasive
and poorly differentiated PDAC. Later, it was shown that
at the mRNA level, SOX2 expression driven by hedge-
hog-EGFR signaling is necessary for tumor-initiating
pancreatic cancer cells
[55]
. Very recently, the molecular
mechanism underlying SOX2 regulation of pancreatic
cancer stemness has been elucidated. Using primary hu-
man cancer tissues and cell lines (L3.6, Bxpc3, CFPAC-1,
Panc1 and Panc04.03), our group demonstrated a critical
role for SOX2 in promoting cell proliferation, dedifferen-
tiation and impartment of stem cell-like features to pan-
creatic cancer cells
[38]
. In particular, SOX2 gene suppres-
sion arrested cells at the G1 phase and its overexpression
alone was suffcient to drive cell proliferation by facilitat-
ing G1/S transition. Mechanistically, G1 arrest in SOX2
knockdown cells is associated with a marked induction
of p21
Cip1
and p27
Kip1
, two key cyclin/CDK inhibitors,
whereas SOX2 overexpression induces G1/S-specifc cy-
clin D3 expression. All of three cell cycle regulators were
identifed as bona fde SOX2 regulatory targets. SOX2 also
confers pancreatic cancer cell stemness and its overex-
pression alone is sufficient to drive sphere-formation
and expression of CSC markers
[7,38,45,56]
, as well as induce
EMT drivers such as Snail, Slug and Twist (Figure 2).
Consistently, loss of miR-145 elevates SOX2 and impairs
differentiation in pancreatic tumors
[57]
.
It is now evident that the core stem cell factors
OCT4
[16]
, SOX2
[58]
,

and NANOG
[59]
play essential roles
in the maintenance of pluripotency and self-renewal of
ESCs, ASCs, iPSCs and CSCs. These stem cell factors
promote self-renewal by interacting with other transcrip-
tion factors (Stat3, Hesx1, Zic3), critical cell signaling
molecules (Hedgehog, TCF3, FGF2, LEFTY2)
[60]
, and
have been found aberrantly expressed in several types of
human tumors including pancreatic cancer
[61-63]
. Although
ESCs and CSCs share the property of self-renewal, they
also reveal distinct features in that ESCs favor differen-
tiation, whereas CSCs are more biased toward prolifera-
tion and inhibition of apoptosis. In particular, SOX2
has demonstrated OCT4 and/or NANOG independent
activity in pancreatic cancer cells in promoting cell pro-
liferation, survival, and/or de-differentiation
[38]
. Recent
work by Polvani et al
[47]
further supports this statement
demonstrating that OCT4 silencing reduces OCT4 and
increases NANOG, but does not alter SOX2 expression.
CSCs AS TARGET FOR CANCER
THERAPY
SOX2 immunoreactivity has been demonstrated in
PanIN lesions, as well as moderately and poorly dif-
ferentiated tumors, which is consistent with previous
reports showing an enrichment of SOX2 in pancreatic
CSCs
[64]
, as well as a decreased expression after anti-ESCs
therapies
[55,65]
. Since SOX2 appears to be a key factor
aberrantly expressed in PDAC and confers CSCs-like
properties
[38]
, targeting SOX2 or its upstream regulator(s)
may be exploited for therapeutic purposes. Recent re-
ports demonstrate that using poly (lactide-co-glucolide)
to knockdown DCLK1 results in an increase in miR-145
associated with decreased puripotency factors including
SOX2, and consequently, tumor growth arrest in xeno-
grafts
[57,66]
. Lastly, data from Sobrevals et al
[67]
elucidates
the relevance of uPAR-controlled oncolytic adenoviruses
in the elimination of pancreatic CSCs. Along these lines,
C-Met inhibitors have been demonstrated to overcome
gemcitabine resistance and stem cell signaling through
downregulation of CSC markers including SOX2
[65]
.
Strategies to target CSCs for cancer therapy have been
proposed and are under investigation. For instance, met-
formin directed against pancreatic CSC has been shown
to reduce tumor burden and prevent disease progres-
sion
[68]
. Disulfram, an ALDH inhibitor, was tested in vitro
and in vivo demonstrated a capacity to suppress pancreatic
CSCs
[69]
. Promising results suggest that HAb18G/CD47
or Phospho-valproic acid (MDC-1112) could also be a
promising target in pancreatic cancer surrogating anti-
STAT3 therapies
[70,71]
. More recently, HAb18G/CD147
has been identified as another promising therapeutic
target for highly aggressive pancreatic cancer and a sur-
rogate marker in the STAT3-targeted molecular therapies,
such as by phospho-valproic acid (MDC-1112), a novel
valproic acid derivative. Since targeting CSCs has been
demonstrated to be a viable therapeutic strategy against
pancreatic cancer, a better undertanding of OCT4,
NANOG and particularly SOX2 on their expression and
regulatory circuitry in PDAC will facilitate the design of
individualized therapies for PDAC patients.
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P- Reviewers: Scaggiante B, Vickers MM S- Editor: Qi Y
L- Editor: A E- Editor: Ma S
P- Reviewers Bener A S- Editor Wen LL L- Editor Cant MR E- Editor Ma S
P- Reviewers Bener A S- Editor Song XX L- Editor Stewart GJ E- Editor Ma S
Herreros-Villanueva M et al . Stem cell factors and pancreatic cancer
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