Definition of Prostaglandin E2–EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth

Abstract

Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation-and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFa and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFa, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFa, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.

Prolonged activation of cAMP signaling leads to endothelial barrier disruptionviatranscriptional repression ofRRAS

“…For instance, prostaglandins are highly elevated in the tumor stroma of many types of cancer, including breast cancer (45, 53–55). We found nuclear accumulation of phosphorylated CREB1 in the tumor vascular endothelium of human breast cancer, indicating chronic activation of cAMP signaling in these vessels.…”

Prostaglandin‐cytokine crosstalk in chronic inflammation

“…Ma et al . found extensive neutrophil infiltration in association with tumour development in the colon in the AOM/DSS‐induced colitis‐associated colorectal cancer model and reported that PGE 2 was involved in this sustained neutrophil accumulation (Ma et al ., ). Infiltrating neutrophils highly express EP 2 receptors and an EP 2 receptors agonist and TNF‐α synergistically induced the expression of various inflammation‐related genes in vitro in primary cultured neutrophils, which included COX‐2, IL‐6 and CXCL1, through NF‐κB.…”

“…Infiltrating neutrophils highly express EP 2 receptors and an EP 2 receptors agonist and TNF‐α synergistically induced the expression of various inflammation‐related genes in vitro in primary cultured neutrophils, which included COX‐2, IL‐6 and CXCL1, through NF‐κB. A deficiency in EP 2 receptors or EP 2 antagonism abolished neutrophil infiltration, suppressed the expression of inflammatory genes including CXCL1 and decreased the number of colon tumours (Ma et al ., ). These findings are consistent with the preceding study by Katoh et al .…”

Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors

“…It was also found that disease-specific mortality in colorectal cancer showed a negative correlation with EP2 receptor expression (5,6). Moreover, several studies have displayed that EP2-knockout mice have reduced tumor growth compared with tumors in wild-type mice (7)(8)(9)(10)(11). Therefore, we speculate that the differences in gene expression among tumors growing on EP2-knockout mice versus tumors growing on wild-type mice may indicate important signaling between the tumor and stroma tissue, which subsequently determines tumor growth and progression.…”