A
Putative Link Among the Triad: Inflammation, Reprogramming, and Cancer
Shigeo Masuda
Shigeo
Masuda, Gene Expression Laboratory, The Salk Institute for
Biological Studies, La Jolla, CA, the United States
Shigeo
Masuda, Sanford Consortium
for Regenerative Medicine, La Jolla, CA, the United States
Correspondence
to: Shigeo Masuda, Gene Expression Laboratory, The Salk Institute for
Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, the
United States. smasuda@salk.edu
Tel: +01-858-453-4100
Fax:
+01-858-453-2573
Received: Apirl
11, 2013
Revised: May 7, 2013
Accepted:
May 9, 2013
Published
online: July 18, 2013
ABSTRACT
Induced pluripotent stem cells (iPSCs) are generated during ex vivo
artificial process, referred to as reprogramming process; on the other hand,
reprogramming has been demonstrated to be also involved in human pathological
process in vivo, such as metaplastic change. Moreover, a surprising link
between reprogramming and inflammation has been revealed. In this Editorial at
the triple crossroads, I discuss a novel link among inflammation,
reprogramming, and cancer.
© 2013 ACT. All rights reserved.
Key words: Reprogramming; Inflammation;
Transformation;
Transdifferentiation; Helicobacter pylori; Intestinal metaplasia; TLR3
Masuda S. A Putative Link Among the Triad: Inflammation, Reprogramming, and
Cancer. Journal of tumor 2013; 1(2): 1-2
Available from: URL: http://www.ghrnet.org/index.php/jt
Accumulating evidence suggests that inflammation is
associated with tumorigenesis; for example, Helicobacter pylori induces
chronic inflammation in gastric mucosa, and subsequently there will be
progression from normal gastric mucosa to intestinal metaplasia, from which
adenocarcinoma arises. Recent study indicates that, during inflammation,
emerging reprogramming process results in development of premalignant lesion[1],
which is the first demonstration of reprogramming within human cancer. Another
interesting paper published recently shows that inflammation (innate immunity)
and nuclear reprogramming are linked via toll-like receptor-3 (TLR3) activation[2].
As shown in figure 1, there is a possibility that the triad (inflammation,
reprogramming, and cancer) might be closely related, and in this editorial, the
details would be overviewed, followed by the discussion on unanswered
questions.
The article by Fujii et al[1] demonstrates that
CDX1-induced stemness-associated reprogramming factors (SALL4 and KLF5) convert
gastric epithelial cells into intestinal epithelial cells. Helicobacter pylori-induced
chronic gastritis is a major cause of gastric intestinal metaplasia, from which
intestinal-type gastric adenocarcinoma arises. Metaplasia is histological
change from one tissue type to another, and is associated with neoplastic
transformation via metaplasia-dysplasia-carcinoma sequence. Helicobacter
pylori CagA aberrantly stimulates ¦Â-catenin signaling and induces Wnt
target genes including CDX1. It would be significant that the study by Fujii et
al[1] has shown that CDX1 induces stemness-associated
reprogramming factors SALL4 and KLF5, which is the first demonstration of the
involvement of reprogramming factors in metaplastic changes. Although generation of induced
pluripotent stem cells (iPSCs) is known to be ex vivo artificial process, it
has been shown that reprogramming process is also involved in pathological
process in vivo, such as metaplastic change. Collectively, chronic
infection with Helicobacter pylori could lead to gastric intestinal
metaplasia via CDX1-induced stemness-associated reprogramming factors SALL4 and
KLF5. As Fujii et al[1] discussed, cancer stem cells possess
properties that are shared in common with tissue stem/progenitor cells,
suggesting that acquisition of stemness traits may link to cell transformation,
and that a transition through intestinal stem/progenitor-like states via
dedifferentiation may predispose cells to undergo neoplastic changes; which may
explain why intestinal metaplasia is a precancerous lesion of the stomach[1].
Next, Lee et al[2]
have recently revealed that activation of inflammatory pathways is required for
efficient reprogramming. TLR3 activation is identified as a factor for
efficient nuclear reprogramming, indicating an unexpected link between innate
immunity and nuclear reprogramming[2]. Indeed, knockdown of TLR3
pathway inhibits nuclear reprogramming. Furthermore, TLR3 activation induces an
open chromatin state, which increases cell plasticity as epigenetic modifiers.
Lee et al[2] speculate that this cell state may enhance
induction of pluripotency, transdifferentiation, or even malignant
transformation, and the authors refer to this state as ¡°transflammation¡±. Regarding transdifferentiation, as Ding et
al[3] first demonstrated, short transient expression of
reprogramming factors is enough to induce a partially reprogrammed state that
is suitable for conversion into specific cell types. This is known as lineage
conversion by plastic induction.
Based on these
findings, it would be interesting to clarify whether TLR3 activation is also
involved in intestinal metaplasia, especially in human gastric samples, in the
study by Fujii et al[1]. The hypothesis is that inflammation
by innate immunity would promote reprogramming in cooperation with SALL4 and
KLF5, which leads to intestinal metaplasia. If so, knockdown of TLR3 might
result in change of phenotype, implying the possibility that anti-inflammatory
strategy would be linked with prevention of precancerous lesion.
It has been suggested that infection with Helicobacter pylori is
associated with activation of TLR2, 4, 5[4], but not TLR3. Since
activation of TLR3 is known to be induced by infection of virus including EB
virus, and since EB virus-encoded small RNA (EBER) induces signaling from TLR3[5],
it would be also interesting to examine whether the presence of EBER would
enhance reprogramming in cooperation with SALL4 and KLF5 and would accelerate
the process of intestinal metaplasia.
As the authors
mentioned[1], SALL4 positively regulates Oct4, c-Myc, Sox2, and
Klf4. It would be also helpful if expression of iPSC-four-factors in human
gastric samples would be clarified in future. Another interesting question to be
addressed is whether local invasion (as well as distant metastasis) from a
malignant tumor with a special histological type may result from reprogramming of
normal cells. Implication of
reprogramming in the pathogenesis should be clarified.
Collectively, the first documentation of reprogramming in human disease
would be outstanding, and it would be believed that modulation in the
plasticity of lineage commitment might contribute to prevention of cancer in
the near future.
REFERENCES
1 Fujii Y, Yoshihashi K, Suzuki H, Tsutsumi S, Mutoh
H, Maeda S, Yamagata Y, Seto Y, Aburatani H, Hatakeyama M (2012) CDX1 confers
intestinal phenotype on gastric epithelial cells via induction of
stemness-associated reprogramming factors SALL4 and KLF5. Proc Natl Acad Sci
USA 109: 20584-20589
2 Lee J, Sayed N, Hunter A, Au KF, Wong WH, Mocarski
ES, Pera RR, Yakubov E, Cooke JP (2012) Activation of innate immunity is
required for efficient nuclear reprogramming. Cell 151: 547¨C558
3 Efe JA, Hilcove S, Kim J, Zhou H, Ouyang K, Wang
G, Chen J, Ding S (2011) Conversion of mouse fibroblasts into cardiomyocytes
using a direct reprogramming strategy. Nat Cell Biol 13: 215¨C222
4 El-Omar EM, Ng MT, Hold GL (2008) Polymorphisms in
Toll-like receptor genes and risk of cancer. Oncogene 27: 244¨C252
5 Iwakiri D, Zhou L, Samanta M, Matsumoto M, Ebihara
T, Seya T, Imai S, Fujieda M, Kawa K, Takada K (2009) Epstein-Barr virus
(EBV)-encoded small RNA is released from
EBV-infected cells and activates signaling from Toll-like receptor 3. J
Exp Med 206: 2091¨C2099
Peer reviewer: Hemant Kumar Bid, PhD, Post Doctoral Scientist-I,
Peter Houghton Lab, Center for childhood cancer and blood diseases (WA-5109),
Nationwide Children¡¯s Hospital, 700 Children¡¯s Drive, Columbus, Ohio, 43205, the United States; Yulan Zhao, MD, PhD,
School of Life Science, North Zhongshan RD 3663, Shanghai City, China.
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