Overexpression of the peroxisome proliferator-activated receptor delta (PPARD) in gastric progenitor cells results in inflammation, dysplasia, and tumor formation in mice, researchers report in the July issue of Gastroenterology. Strategies to reduce PPARD in gastric progenitor cells might lead to treatments for stomach cancer.
Gastric carcinogenesis is associated with chronic inflammation. The 2 most common subtypes are intestinal-type gastric adenocarcinoma (GAC) and diffuse gastric cancer, each with different epidemiologic and pathophysiologic features. GAC is more common and typically develops following chronic inflammation, via intestinal metaplasia, dysplasia, and, finally, invasive adenocarcinoma.
Findings from animal studies indicated that gastric cancer originates from gastric stem cells. Specifically, a small population of quiescent gastric progenitor cells, called villin-expressing gastric progenitor cells (VGPCs), have been proposed as the cell of origin of gastric cancer. It is not known how normal gastric progenitors or stem cells become transformed to promote gastric tumorigenesis.
PPARD is a ligand-dependent nuclear receptor that functions as a transcription factor to regulate cell metabolism, proliferation, and inflammation. PPARD expression is up-regulated in many cancers, although role of PPARD in tumorigenesis is controversial.
A few studies have investigated the roles of PPARD in gastric tumorigenesis. Helicobacter pylori up-regulates PPARD expression in gastric epithelial cells to promote proliferation in humans and mice. GW501516, a PPARD agonist, promotes carcinogen–induced squamous gastric tumor of the forestomach in mice.
Xiangsheng Zuo et al investigated the gastric carcinogenic activity of PPARD by expressing it under control of the villin gene promoter in VGPCs in mice.
Zuo et al found that these mice spontaneously developed gastric tumors that progressed into large, invasive GAC.
Furthermore, PARD expression is increased in human GAC samples compared with paired non-tumor tissues. There was an inverse association between level of PPARD and survival times of patients with GAC.
Expression of PPARD in mouse stomach induced chronic inflammation, loss of parietal cells, spasmolytic polypeptide-expressing metaplasia, and intestinal metaplasia. Zuo et al showed that PPARD overexpression markedly expanded the VGPC population in mice. PPARD-induced gastric tumors contained many VGPCs, even at an early stage in tumor development, in the lesser curvature of the gastric corpus.
PPARD increased expression of the cytokine CCL20 and the chemokine CXCL1 to recruit immune cells into gastric mucosa and promote chronic inflammation. The authors found that PPARD activated the IFNG signaling pathway in the gastric corpus of the mice.
Zuo et al conclude that PPARD overexpression in VGPCs is sufficient to induce gastric tumorigenesis and development of invasive GAC. They also found evidence for a positive-feedback loop between PPARD and IFNG signaling that promotes an inflammatory microenvironment and enables VGPC transformation and gastric tumorigenesis (see figure).
These findings provide new insights into GAC pathogenesis. Strategies to block the activities of PPARD might be developed for chemoprevention or treatment of gastric cancer.