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



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 -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.



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: 547C558

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: 215C222

4    El-Omar EM, Ng MT, Hold GL (2008) Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene 27: 244C252

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: 2091C2099


Peer reviewer: Hemant Kumar Bid, PhD, Post Doctoral Scientist-I, Peter Houghton Lab, Center for childhood cancer and blood diseases (WA-5109), Nationwide Childrens Hospital, 700 Childrens 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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