Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis

Abstract

The activation and differentiation of cancer-associated fibroblasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE2) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE2 signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGFβ–activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast with its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial-to-mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression. Significance: The inflammatory lipid prostaglandin E2 suppresses cancer-associated fibroblast expansion and activation to limit primary mammary tumor growth while promoting metastasis.

Prognostic implications of prostaglandin E-major urinary metabolite in resected non-small-cell lung cancer

“…PGE-MUM is a urinary metabolite of PGE2 and represents the activity of the COX-2 pathway. COX-2 and COX-2-derived PGE2 are reportedly involved in the tumour initiation and proliferation of cancer cells both in vitro and in vivo [ 5 , 16 ]. Several studies performed in clinical settings have shown that COX-2 overexpression is associated with poor prognosis in solid tumours, including NSCLC [ 6 , 17 ].…”

“…Since the lungs play an important role in both the production and metabolism of PGE2, PGE2 levels in clinical specimens are possible indicators of inflammation-associated lung disorders [ 4 ]. Furthermore, COX-2-derived PGE2 is reportedly the most significant prostaglandin involved in cancer progression [ 3 , 5 ]. Although previous studies investigating the association between COX-2/PGE2 activity in tumour tissue and tumour progression have been conducted, accurately measuring its expression in tissue samples has several limitations, such as its rapid degradation, invasiveness of sampling and tumour heterogeneity [ 6 , 7 ].…”

Growth of T-cell lymphoma cells is inhibited by mPGES-1/PGE2 suppression via JAK/STAT, TGF-β/Smad3 and PI3K/AKT signal pathways

“…For lung cancer, it has been shown that CAY10526 restores T-cell immunity via inhibition of mPGES1, contributing to suppression of lung metastasis in Gprc5a-ko mouse model (17). In breast cancer, disruption of PGE2 signaling in CAFs represses carcinoma growth but promotes metastasis (30). Another study support the prognostic value of mPGES1, and suggest targeting this pathway may serve as novel therapeutic avenue for melanoma (22).…”

“…In our group, we reported that c-Jun N-terminal kinase served a role in the mPGES-1/PGE2/EP4/MAPK positive feedback loops in T-ALL cells. Meanwhile, P38 and extracellular signal-regulated kinase 1/2 exerted negative feedback on mPGES-1 (5,30). More recently, we published that mPGES-1/PGE2 promoted proliferation of T-ALL cells by modulating MTDH via the EP3/cAMP/ PKA/CREB pathway (7).…”

“…De Araújo showed that TGF-β dual regulation over COX-2/PGE2 tumor promotion depended on the activation status of H-Ras and Wnt/β-catenin pathways in intestinal tumor cells (29). In breast cancer, TGF-β-activated kinaselike protein (TAK1L), which was identified as a negative regulator for p38MAPK activation, was down-regulated after ablation of mPGES-1 in cancer-associated fibroblasts (CAFs) (30). In our study, the expression of TGF-β and p-Smad3 of Hut78 cells decreased after exposure to CAY10526, indicating that TGF-β/Smad pathway was inhibited via the down-regulation of mPGES-1/PGE2, leading to inhibition of cell proliferation and induction of apoptosis.…”