Activation of epidermal growth factor receptor signaling by the prostaglandin E₂ receptor EP4 pathway during gastric tumorigenesis

Abstract

Cyclooxygenase-2 (COX-2) plays an important role in tumorigene-sis through prostaglandin E 2 (PGE 2) biosynthesis. It has been shown by in vitro studies that PGE 2 signaling transactivates epi-dermal growth factor receptor (EGFR) through an intracellular mechanism. However, the mechanisms underlying PGE 2-induced EGFR activation in in vivo tumors are still not fully understood. We previously constructed transgenic mice that develop gastric tumors caused by oncogenic activation and PGE 2 pathway induction. Importantly, expression of EGFR ligands, epiregulin, amphi-regulin, heparin-binding EGF-like growth factor, and betacellulin, as well as a disintegrin and metalloproteinases (ADAMs), ADAM8, ADAM9, ADAM10, and ADAM17 were significantly increased in the mouse gastric tumors in a PGE 2 pathway-dependent manner. These ADAMs can activate EGFR by ectodomain shedding of EGFR ligands. Notably, the extensive induction of EGFR ligands and ADAMs was suppressed by inhibition of the PGE 2 receptor EP4. Moreover, EP4 signaling induced expression of amphiregulin and epiregulin in activated macrophages, whereas EP4 pathway was required for basal expression of epiregulin in gastric epithelial cells. In contrast, ADAMs were not induced directly by PGE 2 in these cells, suggesting indirect mechanism possibly through PGE 2-associated inflammatory responses. These results suggest that PGE 2 signaling through EP4 activates EGFR in gastric tumors through global induction of EGFR ligands and ADAMs in several cell types either by direct or indirect mechanism. Importantly, gastric tumorigenesis of the transgenic mice was significantly suppressed by combination treatment with EGFR and COX-2 inhibitors. Therefore, it is possible that inhibition of both COX-2 ⁄ PGE 2 and EGFR pathways represents an effective strategy for preventing gastric cancer. (Cancer Sci 2011; 102: 713-719) I t has been established that induction of cyclooxygenase 2 (COX-2) plays an important role in cancer development. (1,2) Genetic mouse model studies indicated that prostaglandin E 2 (PGE 2), a downstream products of COX-2, plays a key role in intestinal tumorigenesis, (3-5) suggesting that the PGE 2 pathway is a possible target for the chemoprevention. On the other hand, epidermal growth factor receptor (EGFR) signaling is also an important target for cancer prevention. (6) Inhibition of EGFR signaling in Apc Min mice, a model of familial adenomatous polyposis, significantly suppresses intestinal polyposis. (7-9) Importantly, combination treatment using an EGFR inhibitor with non-steroidal anti-inflammatory drugs or a COX-2 inhibitor dramatically suppresses intestinal tumorigenesis. (8,9) It has been shown by in vitro experiments that PGE 2 signaling trans-activates EGFR through activation of cSrc (10,11) or MMPs (12) , as well as induction of amphiregulin, an EGFR ligand (13,14) or tumor necrosis factor-a converting enzyme ⁄ a disintegrin and metalloproteinase 17 (TACE/ADAM17), a shedding enzyme for amphiregulin. (15) However, the mechanism responsible for the act...

The inflammatory network in the gastrointestinal tumor microenvironment: lessons from mouse models

“…Although Wnt activation alone is not sufficient for tumor development in K19-Wnt1 mice, Gan mice (compound mutants of K19-Wnt1 and K19-C2mE mice) develop inflammation-associated gastric tumors with 100% incidence [26], indicating that cooperation of the Wnt and PGE 2 pathways can lead to gastric tumorigenesis. Moreover, gastric inflammation and tumorigenesis were significantly suppressed in Gan mice when the mice were treated with a COX-2 inhibitor, celecoxib, or an EP4 receptor inhibitor [48,49]. These results indicate that induction of COX-2/PGE 2 /EP4-induced inflammation is involved in the development of gastric cancer.…”

Cyclooxygenase-2 and Gastric Cancer

“…Interestingly, tumors of the Gan mice have a similar gene expression profile as human intestinal gastric cancer [82]. When Gan mice were treated with celecoxib and ZD1839, an EGFR inhibitor, the tumor volume was decreased by 90% and 76%, respectively, and a combination of both drugs led to a complete regression of the tumors [83]. Additionally, treatment of these mice with an EP4 inhibitor (RQ-00015986/CJ-42794) led to a 76% regression of mean tumor size [84].…”

Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer

“…Furthermore, TGF-b mediates the activation of ADAM protease [34,35]. Tumorassociated MICA is shed by ADAM proteases via TGF-b [36]. Metformin prevents the TGF-b signaling to fully induce mesenchymal cell states in a variety of pathological processes including fibrosis, sclerosis and malignant progression [37].…”