Key Points
-
Metaplasia is the replacement of one differentiated cell type with another mature differentiated cell type that is not normally present in that tissue.
-
Metaplasia, when persistent, can be a precursor to dysplasia, which can in turn progress to carcinoma. As a result, recognition of metaplasia through screening and surveillance modalities is important and could reveal potential strategies for both cancer prevention and therapy.
-
Metaplasia is an adaptive response to injurious agents, which are largely environmental in nature (for example, acid, bile, cigarette smoke and alcohol), but is also influenced by the actions of microorganisms (for example, Helicobacter pylori and human papillomavirus (HPV)).
-
Different types of metaplasia exist, depending upon the tissue source: squamous, intestinal and acinar–ductal.
-
The cell of origin has been postulated to be from the gastric cardia in oesophageal intestinal metaplasia and to be triggered by loss of parietal cells in gastric intestinal metaplasia.
-
Metaplastic cell-autonomous (for example, mutant KRAS signalling) and non-cell-autonomous mechanisms contribute to the development and maintenance of metaplasia.
Abstract
Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar–ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia. A hallmark of metaplasia is a change in cellular identity, and this process can be regulated by transcription factors that initiate and/or maintain cellular identity, perhaps in concert with epigenetic reprogramming. Universally, metaplasia is a precursor to low-grade dysplasia, which can culminate in high-grade dysplasia and carcinoma. Improved clinical screening for and surveillance of metaplasia might lead to better prevention or early detection of dysplasia and cancer.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Slack, J. M. & Tosh, D. Transdifferentiation and metaplasia—switching cell types. Curr. Opin. Genet. Dev. 11, 581–586 (2001).
Jopling, C., Boue, S. & Izpisua Belmonte, J. C. Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nat. Rev. Mol. Cell Biol. 12, 79–89 (2011).
Quinlan, J. M., Colleypriest, B. J., Farrant, M. & Tosh, D. Epithelial metaplasia and the development of cancer. Biochim. Biophys. Acta 1776, 10–21 (2007).
Slack, J. M. Metaplasia and transdifferentiation: from pure biology to the clinic. Nat. Rev. Mol. Cell Biol. 8, 369–378 (2007).
Sharma, P. et al. Dysplasia and cancer in a large multicenter cohort of patients with Barrett's esophagus. Clin. Gastroenterol. Hepatol. 4, 566–572 (2006). One of a number of key studies to estimate the progression of Barrett oesophagus to dysplasia and adenocarcinoma.
Hvid-Jensen, F., Pedersen, L., Drewes, A. M., Sorensen, H. T. & Funch-Jensen, P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N. Engl. J. Med. 365, 1375–1383 (2011).
Leube, R. E. & Rustad, T. J. Squamous cell metaplasia in the human lung: molecular characteristics of epithelial stratification. Virchows Arch. B Cell Pathol. Incl Mol. Pathol. 61, 227–253 (1991).
Dotto, G. P. & Rustgi, A. K. Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell 29, 622–637 (2016).
Park, K. J. & Soslow, R. A. Current concepts in cervical pathology. Arch. Pathol. Lab Med. 133, 729–738 (2009).
Regauer, S. & Reich, O. CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high-grade cervical intraepithelial neoplasia (CIN III). Histopathology 50, 629–635 (2007).
Zsemlye, M. High-grade cervical dysplasia: pathophysiology, diagnosis, and treatment. Obstet. Gynecol. Clin. North Am. 35, 615–621 (2008).
Psyrri, A. & DiMaio, D. Human papillomavirus in cervical and head-and-neck cancer. Nat. Clin. Pract. Oncol. 5, 24–31 (2008).
Burd, E. M. Human papillomavirus and cervical cancer. Clin. Microbiol. Rev. 16, 1–17 (2003).
Raju, G. C. The histological and immunohistochemical evidence of squamous metaplasia from the myoepithelial cells in the breast. Histopathology 17, 272–275 (1990).
Behranwala, K. A., Nasiri, N., Abdullah, N., Trott, P. A. & Gui, G. P. Squamous cell carcinoma of the breast: clinico-pathologic implications and outcome. Eur. J. Surg. Oncol. 29, 386–389 (2003).
Wang, X. et al. Metaplastic carcinoma of the breast: p53 analysis identified the same point mutation in the three histologic components. Mod. Pathol. 14, 1183–1186 (2001).
Bellino, R. et al. Metaplastic breast carcinoma: pathology and clinical outcome. Anticancer Res. 23, 669–673 (2003).
Alam, M. & Ratner, D. Cutaneous squamous-cell carcinoma. N. Engl. J. Med. 344, 975–983 (2001).
Buezo, G. F., Fernandez, J. F., Tello, E. D. & Diez, A. G. Squamous metaplasia of sebaceous gland. J. Cutan. Pathol. 27, 298–300 (2000).
Chen, X. et al. Oxidative damage in an esophageal adenocarcinoma model with rats. Carcinogenesis 21, 257–263 (2000).
Inayama, M., Hashimoto, N., Tokoro, T. & Shiozaki, H. Involvement of oxidative stress in experimentally induced reflux esophagitis and esophageal cancer. Hepatogastroenterology 54, 761–765 (2007).
Jenkins, G. J. et al. Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: The potential role of anti-oxidants in Barrett's oesophagus. Carcinogenesis 28, 136–142 (2007).
Song, S., Guha, S., Liu, K., Buttar, N. S. & Bresalier, R. S. COX-2 induction by unconjugated bile acids involves reactive oxygen species-mediated signalling pathways in Barrett's oesophagus and oesophageal adenocarcinoma. Gut 56, 1512–1521 (2007).
Feng, C. et al. Diallyl disulfide suppresses the inflammation and apoptosis resistance induced by DCA through ROS and the NF-kappaB signaling pathway in human Barrett's epithelial cells. Inflammation 40, 818–831 (2017).
Feagins, L. A. et al. Mechanisms of oxidant production in esophageal squamous cell and Barrett's cell lines. Am. J. Physiol. Gastrointest Liver Physiol. 294, G411–G417 (2008).
Federico, A., Morgillo, F., Tuccillo, C., Ciardiello, F. & Loguercio, C. Chronic inflammation and oxidative stress in human carcinogenesis. Int. J. Cancer 121, 2381–2386 (2007).
Rustgi, A. K. & El-Serag, H. B. Esophageal carcinoma. N. Engl. J. Med. 371, 2499–2509 (2014). A review article on oesophageal squamous cell carcinoma and adenocarcinoma.
Spechler, S. J. & Souza, R. F. Barrett's esophagus. N. Engl. J. Med. 371, 836–845 (2014).
Shaheen, N. J. et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N. Engl. J. Med. 360, 2277–2288 (2009). A clinical trial that demonstrated efficacy of radiofrequency ablation of Barrett oesophagus with dysplasia.
Schlottmann, F. & Patti, M. G. Current concepts in treatment of Barrett's esophagus with and without dysplasia. J. Gastrointest. Surg. 21, 1354–1360 (2017).
Guthikonda, A. et al. Clinical outcomes following recurrence of intestinal metaplasia after successful treatment of Barrett's esophagus with radiofrequency ablation. Am. J. Gastroenterol. 112, 87–94 (2017).
Zeki, S. S. et al. Clonal selection and persistence in dysplastic Barrett's esophagus and intramucosal cancers after failed radiofrequency ablation. Am. J. Gastroenterol. 108, 1584–1592 (2013).
Noto, J. M. & Peek, R. M. Jr. Helicobacter pylori: an overview. Methods Mol. Biol. 921, 7–10 (2012).
Petersen, C. P., Mills, J. C. & Goldenring, J. R. Murine models of gastric corpus preneoplasia. Cell. Mol. Gastroenterol. Hepatol. 3, 11–26 (2017).
Burclaff, J., Osaki, L. H., Liu, D., Goldenring, J. R. & Mills, J. C. Targeted apoptosis of parietal cells is insufficient to induce metaplasia in stomach. Gastroenterology 152, 762–766 (2017).
Amieva, M. & Peek, R. M. Jr. Pathobiology of helicobacter pylori-induced gastric cancer. Gastroenterology 150, 64–78 (2016).
Jeong, S. et al. Distinct metaplastic and inflammatory phenotypes in autoimmune and adenocarcinoma-associated chronic atrophic gastritis. United Eur. Gastroenterol. J. 5, 37–44 (2017).
Correa, P., Piazuelo, M. B. & Wilson, K. T. Pathology of gastric intestinal metaplasia: clinical implications. Am. J. Gastroenterol. 105, 493–498 (2010). A comprehensive review on gastric intestinal metaplasia.
Lordick, F. et al. Unmet needs and challenges in gastric cancer: the way forward. Cancer Treat. Rev. 40, 692–700 (2014).
Pasechnikov, V., Chukov, S., Fedorov, E., Kikuste, I. & Leja, M. Gastric cancer: prevention, screening and early diagnosis. World J. Gastroenterol. 20, 13842–13862 (2014).
Hamashima, C. et al. The Japanese guidelines for gastric cancer screening. Jpn J. Clin. Oncol. 38, 259–267 (2008).
Choi, K. S. et al. Performance of gastric cancer screening by endoscopy testing through the National Cancer Screening Program of Korea. Cancer Sci. 102, 1559–1564 (2011).
Reichert, M. & Rustgi, A. K. Pancreatic ductal cells in development, regeneration, and neoplasia. J. Clin. Invest. 121, 4572–4578 (2011).
Basturk, O. et al. A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 39, 1730–1741 (2015).
Hegyi, P. & Petersen, O. H. The exocrine pancreas: the acinar–ductal tango in physiology and pathophysiology. Rev. Physiol. Biochem. Pharmacol. 165, 1–30 (2013).
Ying, H. et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 30, 355–385 (2016).
Hosoda, W. & Wood, L. D. Molecular genetics of pancreatic neoplasms. Surg. Pathol. Clin. 9, 685–703 (2016).
Strobel, O. et al. In vivo lineage tracing defines the role of acinar-to-ductal transdifferentiation in inflammatory ductal metaplasia. Gastroenterology 133, 1999–2009 (2007). This study used lineage tracing to demonstrate pancreatic ADM.
De Lisle, R. C. & Logsdon, C. D. Pancreatic acinar cells in culture: expression of acinar and ductal antigens in a growth-related manner. Eur. J. Cell Biol. 51, 64–75 (1990).
Githens, S. et al. Mouse pancreatic acinar/ductular tissue gives rise to epithelial cultures that are morphologically, biochemically, and functionally indistinguishable from interlobular duct cell cultures. In Vitro Cell. Dev. Biol. Anim. 30A, 622–635 (1994).
Rooman, I., Heremans, Y., Heimberg, H. & Bouwens, L. Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro. Diabetologia 43, 907–914 (2000).
Sphyris, N., Logsdon, C. D. & Harrison, D. J. Improved retention of zymogen granules in cultured murine pancreatic acinar cells and induction of acinar–ductal transdifferentiation in vitro. Pancreas 30, 148–157 (2005).
Houbracken, I. et al. Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. Gastroenterology 141, 731–741 (2011).
Davis, M. A. & Reynolds, A. B. Blocked acinar development, E-cadherin reduction, and intraepithelial neoplasia upon ablation of p120-catenin in the mouse salivary gland. Dev. Cell 10, 21–31 (2006).
Ishiyama, N. et al. Dynamic and static interactions between p120 catenin and E-cadherin regulate the stability of cell-cell adhesion. Cell 141, 117–128 (2010).
Kourtidis, A., Ngok, S. P. & Anastasiadis, P. Z. p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression. Prog. Mol. Biol. Transl Sci. 116, 409–432 (2013).
Gutierrez-Gonzalez, L. & Wright, N. A. Biology of intestinal metaplasia in 2008: more than a simple phenotypic alteration. Dig. Liver Dis. 40, 510–522 (2008).
Evans, J. A. & McDonald, S. A. The complex, clonal, and controversial nature of Barrett's esophagus. Adv. Exp. Med. Biol. 908, 27–40 (2016).
Fitzgerald, R. C. et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett's oesophagus. Gut 63, 7–42 (2014).
Spechler, S. J. et al. A summary of the 2016 James W. Freston conference of the american gastroenterological association intestinal metaplasia in the esophagus and stomach: origins, differences, similarities and significance. Gastroenterology 153, e6–e13 (2017). This article comprises a compendium of summaries from a conference on intestinal metaplasia in the oesophagus and stomach.
Quante, M. et al. Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia. Cancer Cell 21, 36–51 (2012). This article presents genetic in vivo lineage-tracing evidence for the cell of origin for Barrett-like metaplasia.
Wang, X. et al. Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell 145, 1023–1035 (2011).
Celli, J. et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99, 143–153 (1999).
McDonald, S. A., Lavery, D., Wright, N. A. & Jansen, M. Barrett oesophagus: lessons on its origins from the lesion itself. Nat. Rev. Gastroenterol. Hepatol. 12, 50–60 (2015).
Lavery, D. L. et al. The stem cell organisation, and the proliferative and gene expression profile of Barrett's epithelium, replicates pyloric-type gastric glands. Gut 63, 1854–1863 (2014).
Vega, M. E. et al. Inhibition of Notch signaling enhances transdifferentiation of the esophageal squamous epithelium towards a Barrett's-like metaplasia via KLF4. Cell Cycle 13, 3857–3866 (2014).
Minacapelli, C. D. et al. Barrett's metaplasia develops from cellular reprograming of esophageal squamous epithelium due to gastroesophageal reflux. Am. J. Physiol. Gastrointest Liver Physiol. 312, G615–G622 (2017).
Sarosi, G. et al. Bone marrow progenitor cells contribute to esophageal regeneration and metaplasia in a rat model of Barrett's esophagus. Dis. Esophagus 21, 43–50 (2008).
Leedham, S. J. et al. Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus. Gut 57, 1041–1048 (2008).
Garman, K. S. et al. Ductal metaplasia in oesophageal submucosal glands is associated with inflammation and oesophageal adenocarcinoma. Histopathology 67, 771–782 (2015).
Kruger, L. et al. Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair. Am J. Physiol. Gastrointest. Liver Physiol. http://dx.doi.org/10.1152/ajpgi.00036.2017 (2017).
Goldenring, J. R., Nam, K. T. & Mills, J. C. The origin of pre-neoplastic metaplasia in the stomach: chief cells emerge from the Mist. Exp. Cell Res. 317, 2759–2764 (2011). This article presents an overview of SPEM.
Lennerz, J. K. et al. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma. Am. J. Pathol. 177, 1514–1533 (2010).
Mills, J. C. & Goldenring, J. R. Metaplasia in the stomach arises from gastric chief cells. Cell. Mol. Gastroenterol. Hepatol. 4, 85–88 (2017).
Hayakawa, Y. et al. Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche. Cancer Cell 28, 800–814 (2015).
Goldenring, J. R. & Nam, K. T. Oxyntic atrophy, metaplasia, and gastric cancer. Prog. Mol. Biol. Transl Sci. 96, 117–131 (2010).
Barker, N., Bartfeld, S. & Clevers, H. Tissue-resident adult stem cell populations of rapidly self-renewing organs. Cell Stem Cell 7, 656–670 (2010).
Leushacke, M. et al. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat. Cell. Biol. 19, 774–786 (2017).
Nam, K. T. et al. Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells. Gut 61, 1678–1685 (2012).
Hayakawa, Y., Fox, J. G. & Wang, T. C. Isthmus stem cells are the origins of metaplasia in the gastric corpus. Cell. Mol. Gastroenterol. Hepatol. 4, 89–94 (2017).
Brembeck, F. H. et al. The mutant K-ras oncogene causes pancreatic periductal lymphocytic infiltration and gastric mucous neck cell hyperplasia in transgenic mice. Cancer Res. 63, 2005–2009 (2003).
Lavery, D. L. et al. Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus. Gut 65, 907–913 (2016).
Nicholson, A. M. et al. Barrett's metaplasia glands are clonal, contain multiple stem cells and share a common squamous progenitor. Gut 61, 1380–1389 (2012). This is an example of a study in human tissues showing that Barrett metaplasia is clonally evolved and contains multipotential stem cells and that division may occur by fission.
Gutierrez-Gonzalez, L. et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 140, 1251–1260 (2011).
McDonald, S. A. et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134, 500–510 (2008).
Pan, Q. et al. Identification of lineage-uncommitted, long-lived, label-retaining cells in healthy human esophagus and stomach, and in metaplastic esophagus. Gastroenterology 144, 761–770 (2013).
McDonald, S. A., Graham, T. A., Lavery, D. L., Wright, N. A. & Jansen, M. The Barrett's gland in phenotype space. Cell. Mol. Gastroenterol. Hepatol. 1, 41–54 (2015).
Liu, K. et al. Sox2 cooperates with inflammation-mediated Stat3 activation in the malignant transformation of foregut basal progenitor cells. Cell Stem Cell 12, 304–315 (2013). This study showed that SOX2 is critical for oesophageal and forestomach tissue identity and patterning.
Giroux, V. et al. Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration. J. Clin. Invest. 127, 2378–2391 (2017). In this study, based on in vivo lineage tracing, a subset of oesophageal basal cells is characterized as being long-lived progenitor cells that contribute to tissue regeneration.
Que, J. et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development 134, 2521–2531 (2007).
Kim, B. M., Buchner, G., Miletich, I., Sharpe, P. T. & Shivdasani, R. A. The stomach mesenchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signaling. Dev. Cell 8, 611–622 (2005).
Chen, Z., Fillmore, C. M., Hammerman, P. S., Kim, C. F. & Wong, K. K. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat. Rev. Cancer 14, 535–546 (2014).
Daniely, Y. et al. Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am. J. Physiol. Cell Physiol. 287, C171–C181 (2004).
Gontan, C. et al. Sox2 is important for two crucial processes in lung development: branching morphogenesis and epithelial cell differentiation. Dev. Biol. 317, 296–309 (2008).
Eda, A. et al. Aberrant expression of CDX2 in Barrett's epithelium and inflammatory esophageal mucosa. J. Gastroenterol. 38, 14–22 (2003).
Phillips, R. W., Frierson, H. F. Jr & Moskaluk, C. A. Cdx2 as a marker of epithelial intestinal differentiation in the esophagus. Am. J. Surg. Pathol. 27, 1442–1447 (2003).
Silberg, D. G. et al. Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122, 689–696 (2002). This study showed that expression of CDX2 in the mouse stomach results in gastric intestinal metaplasia.
Gao, N., White, P. & Kaestner, K. H. Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev. Cell 16, 588–599 (2009). This study showed that conditional knockout of Cdx2 in the mouse intestine results in loss of intestinal identity and in squamous metaplasia.
Coskun, M., Troelsen, J. T. & Nielsen, O. H. The role of CDX2 in intestinal homeostasis and inflammation. Biochim. Biophys. Acta 1812, 283–289 (2011).
Gao, N. & Kaestner, K. H. Cdx2 regulates endo-lysosomal function and epithelial cell polarity. Genes Dev. 24, 1295–1305 (2010).
Pan, F. C. et al. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140, 751–764 (2013).
Pin, C. L., Rukstalis, J. M., Johnson, C. & Konieczny, S. F. The bHLH transcription factor Mist1 is required to maintain exocrine pancreas cell organization and acinar cell identity. J. Cell Biol. 155, 519–530 (2001).
Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012). In this article, the important role of SOX9 in pancreatic ADM and PanIN is elucidated.
Reichert, M. et al. The Prrx1 homeodomain transcription factor plays a central role in pancreatic regeneration and carcinogenesis. Genes Dev. 27, 288–300 (2013).
Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).
Means, A. L. et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132, 3767–3776 (2005).
Zhu, L., Shi, G., Schmidt, C. M., Hruban, R. H. & Konieczny, S. F. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am. J. Pathol. 171, 263–273 (2007).
Miyamoto, Y. et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3, 565–576 (2003).
Kawaguchi, Y. et al. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32, 128–134 (2002).
Miyatsuka, T. et al. Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev. 20, 1435–1440 (2006).
Halbrook, C. J. et al. Mitogen-activated protein kinase kinase activity maintains acinar-to-ductal metaplasia and is required for organ regeneration in pancreatitis. Cell. Mol. Gastroenterol. Hepatol. 3, 99–118 (2017).
Shi, C. et al. KRAS2 mutations in human pancreatic acinar–ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin. Mol. Cancer Res. 7, 230–236 (2009).
Lo, H. G. et al. A single transcription factor is sufficient to induce and maintain secretory cell architecture. Genes Dev. 31, 154–171 (2017).
Capoccia, B. J. et al. The ubiquitin ligase Mindbomb 1 coordinates gastrointestinal secretory cell maturation. J. Clin. Invest. 123, 1475–1491 (2013).
Zhu, L. et al. Inhibition of Mist1 homodimer formation induces pancreatic acinar-to-ductal metaplasia. Mol. Cell. Biol. 24, 2673–2681 (2004).
Weis, V. G. et al. Maturity and age influence chief cell ability to transdifferentiate into metaplasia. Am. J. Physiol. Gastrointest Liver Physiol. 312, G67–G76 (2017).
Karki, A. et al. Silencing Mist1 gene expression is essential for recovery from acute pancreatitis. PLoS ONE 10, e0145724 (2015).
Vasseur, S. et al. Structural and functional characterization of the mouse p8 gene: promotion of transcription by the CAAT-enhancer binding protein alpha (C/EBPalpha) and C/EBPbeta trans-acting factors involves a C/EBP cis-acting element and other regions of the promoter. Biochem. J. 2, 377–383 (1999).
Zenilman, M. E., Tuchman, D., Zheng, Q., Levine, J. & Delany, H. Comparison of reg I and reg III levels during acute pancreatitis in the rat. Ann. Surg. 232, 646–652 (2000).
Ramsey, V. G. et al. The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires Mist1. Development 134, 211–222 (2007).
Nomura, S. et al. Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice. Am. J. Physiol. Gastrointest Liver Physiol. 288, G362–G375 (2005).
Kaz, A. M., Grady, W. M., Stachler, M. D. & Bass, A. J. Genetic and epigenetic alterations in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterol. Clin. North Am. 44, 473–489 (2015).
Kaz, A. M. et al. DNA methylation profiling in Barrett's esophagus and esophageal adenocarcinoma reveals unique methylation signatures and molecular subclasses. Epigenetics 6, 1403–1412 (2011).
Buas, M. F. et al. Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Gut http://dx.doi.org/10.1136/gutjnl-2016-311622 (2016).
Stachler, M. D. et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nat. Genet. 47, 1047–1055 (2015). In this study, the important role of mutant TP53 in Barrett oesophagus is demonstrated.
Ross-Innes, C. S. et al. Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma. Nat. Genet. 47, 1038–1046 (2015). A parallel study to Ref. 125 on deep DNA sequencing of Barrett oesophagus lesions.
Silva, T. C. et al. hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions. BMC Gastroenterol. 12, 85 (2012).
Yang, L. et al. Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 137, 588–597 (2009).
Fukuda, A. et al. Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19, 441–455 (2011).
Petersen, C. P. et al. Macrophages promote progression of spasmolytic polypeptide-expressing metaplasia after acute loss of parietal cells. Gastroenterology 146, 1727–1738 (2014).
Liou, G. Y. et al. Macrophage-secreted cytokines drive pancreatic acinar-to-ductal metaplasia through NF-κB and MMPs. J. Cell Biol. 202, 563–577 (2013).
Liou, G. Y. & Storz, P. Inflammatory macrophages in pancreatic acinar cell metaplasia and initiation of pancreatic cancer. Oncoscience 2, 247–251 (2015).
Liou, G. Y. et al. The presence of interleukin-13 at pancreatic ADM/PanIN lesions alters macrophage populations and mediates pancreatic tumorigenesis. Cell Rep. 19, 1322–1333 (2017).
Kong, J. et al. Immature myeloid progenitors promote disease progression in a mouse model of Barrett's-like metaplasia. Oncotarget 6, 32980–33005 (2015).
Liu, X. et al. Genetic ablation of Smoothened in pancreatic fibroblasts increases acinar–ductal metaplasia. Genes Dev. 30, 1943–1955 (2016). In this study, the importance of SHH signalling from stromal fibroblasts in pancreatic ADM is demonstrated.
Pasca di Magliano, M. et al. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 20, 3161–3173 (2006).
Wang, D. H. et al. Aberrant epithelial-mesenchymal Hedgehog signaling characterizes Barrett's metaplasia. Gastroenterology 138, 1810–1822 (2010).
Konstantinou, D., Bertaux-Skeirik, N. & Zavros, Y. Hedgehog signaling in the stomach. Curr. Opin. Pharmacol. 31, 76–82 (2016).
Rustgi, A. K. Pancreatic fibroblasts smoothen their activities via AKT-GLI2-TGFα. Genes Dev. 30, 1911–1912 (2016).
Pitarresi, J. R. et al. Stromal ETS2 regulates chemokine production and immune cell recruitment during acinar-to-ductal metaplasia. Neoplasia 18, 541–552 (2016).
Grippo, P. J., Nowlin, P. S., Demeure, M. J., Longnecker, D. S. & Sandgren, E. P. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 63, 2016–2019 (2003).
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Choi, E., Hendley, A. M., Bailey, J. M., Leach, S. D. & Goldenring, J. R. Expression of activated ras in gastric chief cells of mice leads to the full spectrum of metaplastic lineage transitions. Gastroenterology 150, 918–930 (2016).
Schmidt, M. K. et al. c-Myc overexpression is strongly associated with metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Dis. Esophagus 20, 212–216 (2007).
de Souza, C. R. et al. MYC deregulation in gastric cancer and its clinicopathological implications. PLoS ONE 8, e64420 (2013).
Lantuejoul, S., Salameire, D., Salon, C. & Brambilla, E. Pulmonary preneoplasia—sequential molecular carcinogenetic events. Histopathology 54, 43–54 (2009).
Hayakawa, Y., Sethi, N., Sepulveda, A. R., Bass, A. J. & Wang, T. C. Oesophageal adenocarcinoma and gastric cancer: should we mind the gap? Nat. Rev. Cancer 16, 305–318 (2016).
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & Depinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).
Orloff, M. et al. Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA 306, 410–419 (2011).
Sun, X. et al. Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas. Mol. Genet. Genom. Med. 4, 407–419 (2016).
Pittayanon, R. et al. The risk of gastric cancer in patients with gastric intestinal metaplasia in 5-year follow-up. Aliment. Pharmacol. Ther. 46, 40–45 (2017).
Acknowledgements
This work was funded in part through the National Cancer Institute and the American Cancer Society. The authors apologize in advance if all relevant references were not able to be cited.
Author information
Authors and Affiliations
Contributions
A.K.R. and V.G. researched the data for the article, wrote the article and reviewed and/or edited the manuscript before its submission. A.K.R. made substantial contributions to the discussions of the content.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Dysplasia
-
A condition in which cells have abnormal cellular architecture, with nuclear atypia, nuclear hyperchromasia and loss of cell polarity.
- Glandular stomach
-
The part of stomach that is responsible for normal physiological functions.
- Parietal cells
-
Also known as oxyntic cells, these are the acid-producing cells in the stomach epithelium.
- Chief cells
-
Pepsinogen- and chymosin-producing cells in the stomach epithelium.
- Atrophic gastritis
-
Loss of segments of the gastric mucosa in the setting of inflammation.
- Spasmolytic polypeptide-expressing metaplasia
-
(SPEM). Metaplastic cells that are marked by spasmolytic polypeptide expression in the stomach epithelium.
- Brush border
-
The small intestinal epithelial microvilli-covered surface that expresses brush border enzymes that mediate the transport of micronutrients from the lumen to within the epithelium.
- Exocrine pancreas
-
Compartments of acinar and ductal cells that secrete and transport digestive enzymes.
- Gastric cardia
-
The small region that constitutes the first part of the stomach and is composed of columnar cells.
- Oesophageal submucosal glands
-
Distinct structures below the oesophageal epithelium that have secretory functions.
- Foveolar hyperplasia
-
A characteristic of reactive gastritis observed in the gastric antrum and body.
Rights and permissions
About this article
Cite this article
Giroux, V., Rustgi, A. Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence. Nat Rev Cancer 17, 594–604 (2017). https://doi.org/10.1038/nrc.2017.68
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc.2017.68
This article is cited by
-
Bridging tissue repair and epithelial carcinogenesis: epigenetic memory and field cancerization
Cell Death & Differentiation (2024)
-
A MTA2-SATB2 chromatin complex restrains colonic plasticity toward small intestine by retaining HNF4A at colonic chromatin
Nature Communications (2024)
-
Decoding spatiotemporal transcriptional dynamics and epithelial fibroblast crosstalk during gastroesophageal junction development through single cell analysis
Nature Communications (2024)
-
Decoding the basis of histological variation in human cancer
Nature Reviews Cancer (2024)
-
Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Nature Communications (2024)