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Updated: Sep 27, 2026
Phospholipid Mediator Induced Transformation in Three-Dimensional Cultures
Published on: July 27, 2022
Host prostaglandin E(2)-EP3 signaling regulates tumor-associated angiogenesis and tumor growth
Hideki Amano1, Izumi Hayashi, Hirahito Endo
1Department of Pharmacology, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
Abstract:
Nonsteroidal antiinflammatories are known to suppress incidence and progression of malignancies including colorectal cancers. However, the precise mechanism of this action remains unknown. Using prostaglandin (PG) receptor knockout mice, we have evaluated a role of PGs in tumor-associated angiogenesis and tumor growth, and identified PG receptors involved. Sarcoma-180 cells implanted in wild-type (WT) mice formed a tumor with extensive angiogenesis, which was greatly suppressed by specific inhibitors for cyclooxygenase (COX)-2 but not for COX-1. Angiogenesis in sponge implantation model, which can mimic tumor-stromal angiogenesis, was markedly suppressed in mice lacking EP3 (EP3(-/-)) with reduced expression of vascular endothelial growth factor (VEGF) around the sponge implants. Further, implanted tumor growth (sarcoma-180, Lewis lung carcinoma) was markedly suppressed in EP3(-/-), in which tumor-associated angiogenesis was also reduced. Immunohistochemical analysis revealed that major VEGF-expressing cells in the stroma were CD3/Mac-1 double-negative fibroblasts, and that VEGF-expression in the stroma was markedly reduced in EP3(-/-), compared with WT. Application of an EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT, but not in EP3(-/-). These results demonstrate significance of host stromal PGE(2)-EP3 receptor signaling in tumor development and angiogenesis. An EP3 receptor antagonist may be a candidate of chemopreventive agents effective for malignant tumors.
Insights
Prostaglandin E2 (PGE2) signaling through the EP3 receptor in the tumor stroma is crucial for cancer development and angiogenesis. Inhibiting this pathway may offer a novel chemopreventive strategy for malignant tumors.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to inhibit cancer development, but their precise mechanisms remain unclear.
- Prostaglandins (PGs) play a role in tumor progression, particularly in angiogenesis and growth.
Purpose of the Study:
- To investigate the role of prostaglandin E2 (PGE2) and its receptors in tumor-associated angiogenesis and tumor growth.
- To identify specific prostaglandin receptors involved in these processes.
Main Methods:
- Utilized prostaglandin (PG) receptor knockout mice, specifically EP3 receptor knockout (EP3(-/-)) mice.
- Employed a tumor implantation model (Sarcoma-180, Lewis lung carcinoma) and a sponge implantation model to mimic tumor-stromal angiogenesis.
- Administered cyclooxygenase (COX)-2 inhibitors and an EP3 receptor antagonist.
- Conducted immunohistochemical analysis to assess vascular endothelial growth factor (VEGF) expression in tumor stroma.
Main Results:
- Tumor growth and angiogenesis were significantly suppressed in EP3(-/-) mice compared to wild-type (WT) mice.
- COX-2 inhibition, but not COX-1 inhibition, suppressed tumor angiogenesis in WT mice.
- VEGF expression in stromal fibroblasts was markedly reduced in EP3(-/-) mice.
- EP3 receptor antagonist inhibited tumor growth and angiogenesis in WT mice, but not in EP3(-/-) mice.
Conclusions:
- Host stromal PGE2-EP3 receptor signaling is critical for tumor development and angiogenesis.
- EP3 receptor antagonists show potential as chemopreventive agents for malignant tumors.
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