Lipocalin-type prostaglandin D synthase-derived PGD2 attenuates malignant properties of tumor endothelial cells.

Abstract

Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-α increased L-PGDS mRNA expression and its product prostaglandin D2 (PGD2 ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD2 to tumor growth and vascularization. Systemic or EC-specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial-to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD2 production in the tumor ECs. This PGD2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Authors: Keisuke Omori, Teppei Morikawa, Akiko Kunita, Tatsuro Nakamura, Kosuke Aritake, Yoshihiro Urade, Masashi Fukayama, Takahisa Murata
• Journal: The Journal of pathology (J Pathol) Vol. 244 Issue 1 Pg. 84-96 (01 2018) ISSN: 1096-9896 [Electronic] England
• PMID: 29124765 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Angiogenesis Inhibitors
• Cytokines
• Lipocalins
• Receptors, Immunologic
• Receptors, Prostaglandin
• Intramolecular Oxidoreductases
• prostaglandin R2 D-isomerase
• Prostaglandin D2
• prostaglandin D2 receptor

Topics

• Angiogenesis Inhibitors (metabolism)
• Animals
• Apoptosis
• Capillary Permeability
• Carcinoma, Squamous Cell (metabolism, pathology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic
• Corneal Neovascularization
• Cytokines (metabolism)
• Endothelial Cells (metabolism)
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Intramolecular Oxidoreductases (genetics)
• Lipocalins (genetics)
• Melanoma (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Neoplasms (prevention & control)
• Prostaglandin D2 (metabolism)
• Receptors, Immunologic (antagonists & inhibitors)
• Receptors, Prostaglandin (antagonists & inhibitors)
• Tumor Microenvironment