Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Abstract

Gastrointestinal hamartomatous polyps in the PeutzJeghers cancer predisposition syndrome and its mouse model (Lkb1؉/؊ ) are presumed to contain all cell types native to the site of their occurrence. This study aimed to explore the pathogenesis of PeutzJeghers syndrome polyposis by characterizing cell types and differentiation of the epithelium of gastric polyps and predisposed mucosa. Both antral and fundic polyps were characterized by a deficit of pepsinogen C-expressing differentiated gland cells (antral gland, mucopeptic, and chief cells); in large fundic polyps, parietal cells were also absent. Gland cell loss was associated with an increase in precursor neck cells, an expansion of the proliferative zone, and an increase in smooth muscle ␣-actin expressing myofibroblasts in the polyp stroma. Lack of pepsinogen C-positive gland cells identified incipient polyps, and even the unaffected mucosa of young predisposed mice displayed an increase in pepsinogen C negative glands (25%; P ‫؍‬ 0045). In addition, in small intestinal polyps, gland cell differentiation was defective, with the absence of Paneth cells. There were no signs of metaplastic differentiation in any of the tissues studied, and both the gastric and small intestinal defects were seen in Lkb1 ؉/؊ mice, as well as polyps from patients with Peutz-Jeghers syndrome. These results identify impaired epithelial differentiation as the earliest pathological sign likely to contribute to tumorigenesis in individuals with inherited Lkb1 mutations. (Am J

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

“…Of these, 1,104 (Supplemental Table 1) were upregulated and 926 (Supplemental Table 2) downregulated more than 2-fold. Our results correlated well with previous microarray analyses of intestinal polyps of PJS patients (21,25) Figure 6C). Importantly, we identified substantially larger significantly altered gene sets ( Figure 5E), probably due to limited patient material used previously (25), highlighting the usefulness of disease models where tissue-specific genetic targeting may reduce the variability and help to distinguish diseasedriving events from secondary changes.…”

“…The Fsp1-expressing cells were almost exclusively distinct from αSMA-expressing populations, with only 2.4% of cells expressing both markers, consistent with previous studies addressing the appearance of these markers in fibroblast populations (20) (Supplemental Figure 4B). Analysis of proliferation in polyps by Ki67 staining indicated an expanded epithelial proliferative zone as previously noted (21), as well as active stromal proliferation (Supplemental Figure 5). These results indicate that clonally expanding stromal myofibroblasts, together with reactively hyperproliferating epithelium, form polyps in PJS.…”

“…As a second approach to identify molecular mechanisms leading to stromal expansion and epithelial hyperproliferation, set derived from PJS (25) or Lkb1 +/-mouse polyps (21,25), to enrich for core changes taking place in more than one analysis ( Figure 5E). From this list of 136 genes (Supplemental Table 3), we selected those whose products are known to be secreted, and which are expressed in the tumorigenic cell type, (myo)fibroblasts.…”

LKB1 signaling in advancing cell differentiation

“…In Peutz-Jeghers polyps, aberrant cell differentiation has been observed both in the mesenchymal [88], and epithelial [122] compartments (Fig. 2).…”

“…Decreased TGFb signaling from the stromal Lkb1-deficient cells to epithelia was identified as a possible mechanism for epithelial hyperproliferation and polyposis [88. ] Studies on the epithelial compartment in PJS patients [123] and Lkb1 ?/-mice [122] have identified an expanded proliferative zone in the epithelium of PJS polyps. Furthermore, the epithelium of gastric and intestinal polyps from PJS patients and Lkb1 ?/-mice demonstrate several Reduced TGF signaling activity has been shown in the stromal smooth muscle lineage cells [88], and may be involved in the stromal-epithelial signaling (right green arrow).…”