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

Abstract

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.

Plasticity of differentiated cells in wound repair and tumorigenesis, part II: skin and intestine

“…Studies in mice reinforce that skin cells can maintain mutations without forming tumors: expressing constitutively active Kras G12D (see Ras superfamily, Box 1 ) in Lrig1 + SCs at the infundibulum of the HF does not induce tumors, unless the epidermis is wounded with a biopsy punch ( Page et al, 2013 ). This is similar to the finding that Kras G12D is unable to drive pancreatic cancer without induced inflammation ( Guerra et al, 2007 ), as discussed in Part I of this Review ( Burclaff and Mills, 2018 ). This conserved need for wounding highlights how mutations can be stored in the cellular lineages long term, until some aspect of the recovery response, such as changes within the SCs or in their progeny, initiates tumor formation.…”

“…They supplied no experimental second ‘hit’, yet still observed SCC formation at sites of frequent wounding, such as the base of the tail and around the ear tags ( Bailleul et al, 1990 ). Thus, wounding was also necessary to promote tumorigenesis in this system, akin to earlier experiments showing that repeated mechanical injury (cutting) is sufficient to promote tumor initiation in skin primed with a topical carcinogen ( Förstenberger et al, 1989 ) and in agreement with our understanding of tumorigenesis in pancreas and stomach ( Burclaff and Mills, 2018 ). Differentiated cells could also serve as cancer cells of origin when mutant Hras expression was forced under the regulation of the Krt1 promoter, which drives expression in suprabasal cells or fate-determined, post-mitotic basal cells ( Greenhalgh et al, 1993 ).…”

“…In addition to the aforementioned plasticity of qSCs and progenitors, a recent report shows that irradiation can revert mature Paneth cells to a proliferative state in which they give rise to other intestinal lineages via a Notch1-mediated mechanism ( Yu et al, 2018 ). Paneth cells are close relatives to gastric chief cells and pancreatic acinar cells ( Burclaff and Mills, 2018 ), with all three being large, long-lived, normally non-proliferative secretory cells that express the transcription factor Mist1 ( Lo et al, 2017 ). The authors show that Yap1 is upregulated in these Paneth cells as they dedifferentiate, although it has not yet been shown whether they undergo the stages of paligenosis as seen in their gastric and pancreatic counterparts ( Willet et al, 2018 ).…”

“…The well-defined cell types and array of lineage-tracing ( Box 1 ) markers available within these organs have pointed to plasticity at multiple levels. Thus, our picture of cell interconversions and individual cell ontogenies in these organs is somewhat at a ‘higher resolution’ than in the pancreas and stomach (as discussed in Burclaff and Mills, 2018 ). For example, in the intestines, multiple molecular markers have identified possible progenitor and quiescent SC (qSC) populations that can replace the constitutive Lgr5 + SC, which themselves can be studied by several markers and promoter tools, following injury.…”

“…In Part I of this Review ( Burclaff and Mills, 2018 ), we discussed how long-lived, largely post-mitotic secretory cells in the stomach and pancreas can reprogram to re-enter the cell cycle after injury following a seemingly remarkably conserved process that we have termed paligenosis ( Willet et al, 2018 ). We proposed that an unfortunate consequence of long-lived cells having the potential to undergo rounds of paligenosis and redifferentiation is that they might accumulate and store mutations until a final tumor-initiating mutation induces a dysplastic change that locks cells in a proliferative, pre-cancerous state ( Fig.…”