A chief source of cancer and repair in stomachs

Radyk, Megan D.; Mills, Jason C.

doi:10.15252/embj.201797519

Cited by 6 publications

(4 citation statements)

References 12 publications

(34 reference statements)

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“…In some mouse models, however, SPEM can progress to proliferative lesions with histological abnormalities resembling human dysplasia ( Box 2 ) ( Nomura et al, 2004 ; Petersen et al, 2017b ). The architecture of the gastric unit is beneficial for studies characterizing the initial steps of gastric tumorigenesis, as the spatial separation between the normal isthmal and injury-induced basal proliferation zones allows for inferences to be made about the cells of origin for metaplasia and dysplasia ( Radyk and Mills, 2017 ). Multiple recent studies have shown how proliferative dysplasia can be induced solely by expressing activated Kirsten rat sarcoma (KRAS; see ‘Ras genes’, Box 2 ) using multiple promoters found in chief cells ( Choi et al, 2016 ; Leushacke et al, 2017 ; Matsuo et al, 2017 ).…”

Section: Stomachmentioning

confidence: 99%

Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas

Burclaff

Mills

2018

Disease Models &Amp; Mechanisms

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For the last century or so, the mature, differentiated cells throughout the body have been regarded as largely inert with respect to their regenerative potential, yet recent research shows that they can become progenitor-like and re-enter the cell cycle. Indeed, we recently proposed that mature cells can become regenerative via a conserved set of molecular mechanisms (‘paligenosis’), suggesting that a program for regeneration exists alongside programs for death (apoptosis) and division (mitosis). In two Reviews describing how emerging concepts of cellular plasticity are changing how the field views regeneration and tumorigenesis, we present the commonalities in the molecular and cellular features of plasticity at homeostasis and in response to injury in multiple organs. Here, in part 1, we discuss these advances in the stomach and pancreas. Understanding the extent of cell plasticity and uncovering its underlying mechanisms may help us refine important theories about the origin and progression of cancer, such as the cancer stem cell model, as well as the multi-hit model of tumorigenesis. Ultimately, we hope that the new concepts and perspectives on inherent cellular programs for regeneration and plasticity may open novel avenues for treating or preventing cancers.

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Section: Stomachmentioning

confidence: 99%

Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas

Burclaff

Mills

2018

Disease Models &Amp; Mechanisms

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“…Chronically, however, ongoing damage and long-term metaplasia are associated with and may fuel the majority of gastric and pancreatic adenocarcinomas (Mills & Sansom, 2015;Giroux & Rustgi, 2017;Storz, 2017). In both organs, the cells of origin for the metaplastic, proliferating epithelial cells are thought to be differentiated secretory cells (zymogenic chief cells in the stomach and acinar cells in the pancreas) that reprogram to re-enter the cell cycle (Mills & Sansom, 2015;Murtaugh & Keefe, 2015;Radyk & Mills, 2017).…”

Section: Introductionmentioning

confidence: 99%

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

et al. 2018

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In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as ; and finally reactivate mTORC1 and re-enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.

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“…In particular, the evidence for chief cell plasticity has been demonstrated by lineage tracing using Cre ERT2 driven by the differentiated chief cell marker Mist1 171 , elements of the Runx1 promoter (known as eR1) 190 , Troy ( Tnfrsf19 ) 191 , and most recently Lgr5 169 . Using an expression cassette that better matches endogenous expression of the Lgr5 gene, Barker and colleagues discovered that LGR5 labels chief cells deep within the gland 169,193 . Additionally, Mist1 , eR1, and Lgr5 have all been shown to cause metaplasia and even dysplasia if these promoters drive expression of an oncogenic K-Ras.…”

Section: Introductionmentioning

confidence: 99%

Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer

Sáenz

Mills

2018

Nat Rev Gastroenterol Hepatol

105

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Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.

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A chief source of cancer and repair in stomachs

Cited by 6 publications

References 12 publications

Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas

Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer

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