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Are Gastric and Esophageal Metaplasia Relatives? The Case for Barrett’s Stemming from SPEM

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Abstract

Chronic injury and inflammation in the esophagus can cause a change in cellular differentiation known as metaplasia. Most commonly, the differentiation changes manifest as Barrett’s esophagus (BE), characterized by the normal stratified squamous epithelium converting into a cuboidal–columnar, glandular morphology. BE cells can phenotypically resemble specific normal cell types of the stomach or intestine, or they can have overlapping phenotypes in disorganized admixtures. The stomach can also undergo metaplasia characterized by aberrant gastric or intestinal differentiation patterns. In both organs, it has been argued that metaplasia may represent a recapitulation of the embryonic or juvenile gastrointestinal tract, as cells access a developmental progenitor genetic program that can help repair damaged tissue. Here, we review the normal development of esophagus and stomach, and describe how BE represents an intermixing of cells resembling gastric pseudopyloric (SPEM) and intestinal metaplasia. We discuss a cellular process recently termed “paligenosis” that governs how mature, differentiated cells can revert to a proliferating progenitor state in metaplasia. We discuss the “Cyclical Hit” theory in which paligenosis might be involved in the increased risk of metaplasia for progression to cancer. However, somatic mutations might occur in proliferative phases and then be warehoused upon redifferentiation. Through years of chronic injury and many rounds of paligenosis and dedifferentiation, eventually a cell with a mutation that prevents dedifferentiation may arise and clonally expand fueling stable metaplasia and potentially thereafter acquiring additional mutations and progressing to dysplasia and cancer.

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Acknowledgments

Support provided by the NIDDK R01s (DK094989, DK105129, DK110406), Alvin J. Siteman Cancer Center/Barnes Jewish Hospital Foundation Cancer Frontier Fund, NIH NCI P30 CA091842, The Barnard Trust, and DeNardo Education and Research Foundation Grants to J.C.M.

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  1. Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Ramon U. Jin

  2. Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Jason C. Mills

  3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA

    Jason C. Mills

  4. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Jason C. Mills

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Jin, R.U., Mills, J.C. Are Gastric and Esophageal Metaplasia Relatives? The Case for Barrett’s Stemming from SPEM. Dig Dis Sci 63, 2028–2041 (2018). https://doi.org/10.1007/s10620-018-5150-0

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