PPARdelta overexpression drives transformation of multiple gastric progenitor and stem cells and tumorigenesis in mice

Background Peroxisome proliferator-activated receptor delta (PPARdelta) is upregulated in many types of human cancers, including gastric adenocarcinoma (GAC). Elevated PPARdelta expression correlates positively with GAC grade and stage, and negatively with patient survival. Overexpression of PPARdelta in villin-positive gastric progenitor cells (VGPCs) has been shown to spontaneously induce GAC in villin-PPARdelta mice through CCR20/CCR6 axis-mediated remodeling of the gastric tumor microenvironment. Lgr5-positive gastric stem cells (LGSCs), located in the gastric antrum and corpus glands, have also been widely studied for their role in GAC initiation and progression. However, whether this PPARdelta-driven GAC is specific to particular cell types or models remains largely unknown. Methods A new conditional transgenic PPARdelta overexpression mouse line (CAG-LSL-PPARdelta) was generated and subsequently crossed with villin-Cre or Lgr5-EGFP-IRES-CreERT2 mice (Lgr5-CreERT2) to generate CAG-LSL-PPARdelta; villin-Cre (PPARdelta villin-cre ) or CAG-LSL-PPARdelta; Lgr5-CreERT2 (PPARdelta lgr5-creERT2 ) mice, in which PPARdelta was overexpressed in VGPCs or LGSCs following tamoxifen induction. PPARdelta villin-cre mice (n=15) and their controls (villin-Cre, n=12) were followed up until 45 weeks of age, whereas PPARdelta lgr5-creERT2 (n=16) and their controls (Lgr5-CreERT2, n=14) were observed for 45 weeks post-tamoxifen induction. Additionally, villin-PPARdelta mice were bred with CCR6 knockout (CCR6-KO) mice to generate villin-PPARdelta; CCR6-KO mice, which along with villin-PPARdelta mice, were monitored until 35 weeks of age. All mice were evaluated for tumor multiplicity and subjected to histopathological examination. Results Gastric hyperplasia and/or low-grade dysplasia occurred in the corpus of 100% of PPARdelta villin-cre and PPARdelta lgr5-creERT mice. High-grade dysplasia and/or locally invasive GAC were found in the corpus of 27% (4/15) of PPARdelta villin-cre , in both the corpus and antrum of 13% (2/16), and in the corpus of 19% (3/16) of PPARdelta lgr5-creERT2 , whereas none of the control mice developed these lesions. Chronic inflammation was present in gastric lesions and positively correlated with tumor progression from hyperplasia to locally invasive GAC. CCR6 KO markedly suppressed PPARdelta overexpression in VGPCs-induced gastric inflammation and tumorigenesis. Conclusions PPARdelta overexpression in both VGPCs and LGSCs induces chronic gastric inflammation and tumor formation. PPARdelta, CCR6, VGPCs, and LGSCs may represent potential therapeutic targets for GAC.