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Lipocalin‐type prostaglandin D synthase‐derived PGD 2 attenuates malignant properties of tumor endothelial cells
Author(s) -
Omori Keisuke,
Morikawa Teppei,
Kunita Akiko,
Nakamura Tatsuro,
Aritake Kosuke,
Urade Yoshihiro,
Fukayama Masashi,
Murata Takahisa
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4993
Subject(s) - lipocalin , angiogenesis , prostaglandin d2 , melanoma , prostaglandin , tumor microenvironment , cancer research , apoptosis , endothelial stem cell , cytokine , in situ hybridization , biology , tumor progression , endocrinology , chemistry , medicine , immunology , cancer , in vitro , messenger rna , biochemistry , tumor cells , gene
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 D 2 (PGD 2 ) in human normal ECs. We also investigated the contribution of L‐PGDS–PGD 2 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 PGD 2 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 PGD 2 production in the tumor ECs. This PGD 2 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.