Omori Keisuke, Morikawa Teppei, Kunita Akiko, Nakamura Tatsuro, Aritake Kosuke, Urade Yoshihiro, Fukayama Masashi, Murata Takahisa
Department of Animal Radiology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
J Pathol. 2018 Jan;244(1):84-96. doi: 10.1002/path.4993. Epub 2017 Nov 10.
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 (PGD ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD 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 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 production in the tumor ECs. This PGD 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.
内皮细胞（ECs）是肿瘤微环境的关键组成部分。与正常组织中的内皮细胞相比，它们具有异常特征。在此，我们发现从小鼠黑色素瘤分离的内皮细胞中脂质运载蛋白型前列腺素D合酶（L-PGDS）mRNA（Ptgds）表达显著增加。小鼠黑色素瘤的免疫染色显示内皮细胞中有L-PGDS蛋白表达。原位杂交也显示人黑色素瘤和口腔鳞状细胞癌的内皮细胞中有L-PGDS（PTGDS）mRNA表达。体外实验表明，用肿瘤细胞衍生的白细胞介素-1和肿瘤坏死因子-α刺激可增加人正常内皮细胞中L-PGDS mRNA表达及其产物前列腺素D（PGD）。我们还研究了L-PGDS-PGD对肿瘤生长和血管生成的作用。L-PGDS的全身或内皮细胞特异性缺乏加速了小鼠黑色素瘤的生长，而用PGD受体激动剂DP1（BW245C，0.1mg/kg，每天腹腔注射两次）治疗则可减轻这种生长。形态学和体内研究表明，内皮细胞L-PGDS缺乏导致肿瘤内皮细胞的功能变化，如肿瘤中血管通透性加速、血管生成和内皮-间充质转化（EndMT），进而减少肿瘤细胞凋亡。这些观察结果表明，肿瘤细胞衍生的炎性细胞因子增加肿瘤内皮细胞中L-PGDS表达及随后的PGD产生。这种PGD作为肿瘤内皮细胞致瘤性变化的负调节因子。版权所有©2017大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版。
