Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence

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.

Figure 1. Squamous metaplasia

In tissue columnar cells (for example, in the lung or cervix), external stimuli (for example, low vaginal pH in the cervix and cigarette smoke in the lung) promote the conversion to metaplastic squamous cells, which stratify. In the lung, columnar cells are identified by the expression of homeobox protein Nkx2.1 (NKX2-1), and squamous cells are enriched for p63 and SRY-box 2 (SOX2), similar to oesophageal basal cells and their marked expression of p63 and SOX2.

Figure 2. Intestinal metaplasia in the oesophagus

The normal oesophageal squamous epithelial proliferative basal cells (p63⁺ and SRY-box 2 (SOX2)⁺) undergo early and terminal differentiation as they migrate towards the luminal surface. In concert with acid or bile reflux and pro-inflammatory stimuli (for example, interleukin 6 (IL-6)–signal transducer and activator of transcription 3 (STAT3)), incomplete intestinal metaplasia (presence of columnar cells and goblet cells and absence of Paneth cells and enteroendocrine cells) appears. Goblet cells produce mucins, which are cytoprotective. Mesenchymal homeobox protein BarH-like 1 (BARX1) and bone morphogenetic protein 4 (BMP4) (induced by epithelial sonic hedgehog (SHH)) are critical for the transition from the squamous cell lineage to the intestinal (columnar) cell lineage. Caudal type homeobox 2 (CDX2) is critical for the induction of columnar cells, and Notch signalling is a key pathway for the maintenance of the columnar cell lineage. Genomic studies have revealed thatTP53 mutation is important in the earliest dysplastic clones. In this figure, the underlying premise is on the morphological and molecular changes that occur, but the cell of origin is not implied.

Figure 3. Acinar–ductal metaplasia

Normal pancreatic acinar cells, which compose the bulk of the pancreatic parenchyma and express pancreas transcription factor 1 subunit α (PTF1A) and MIST1, can convert into a ductal-cell-like state, which is referred to as acinar–ductal metaplasia (ADM). Pro-inflammatory stimuli from T cells, macrophages and myeloid-derived suppressor cells (MDSCs) and mutant KRAS are critical for the appearance of ADM lesions. These lesions are enriched for paired mesoderm homeobox protein 1 (PRRX1) and SRY-box 9 (SOX9) transcription factors, as well as for Nestin⁺ and the transcription factor HES1⁺ cells, the latter owing to active Notch signalling. Pancreatic fibroblasts are a source of sonic hedgehog (SHH), which slows ADM formation.

Figure 4. Spasmolytic polypeptide-expressing metaplasia and gastric intestinal metaplasia

The gastric epithelium harbours chief cells at the base, underneath acid-producing parietal cells, progenitor cells (or stem cells) and surface cells. In the face of Helicobacter pylori infection, there is parietal cell loss and chronic inflammation. One pathway results in foveolar hyperplasia and spasmolytic polypeptide-expressing metaplasia (SPEM), which might be a precursor to intestinal metaplasia (IM, indicated by the dashed arrow). Another pathway leads directly to IM. Both SPEM and IM are precursors to dysplasia and later adenocarcinoma. Please refer to the main text for a discussion of cell of origin.