Lysophosphatidic Acid Receptor 4 Activation Augments Drug Delivery in Tumors by Tightening Endothelial Cell-Cell Contact

• Published in: Cell reports (Cambridge) 2017-08, Vol.20 (9), p.2072-2086
• Main Authors: Takara, Kazuhiro, Eino, Daisuke, Ando, Koji, Yasuda, Daisuke, Naito, Hisamichi, Tsukada, Yohei, Iba, Tomohiro, Wakabayashi, Taku, Muramatsu, Fumitaka, Kidoya, Hiroyasu, Fukuhara, Shigetomo, Mochizuki, Naoki, Ishii, Satoshi, Kishima, Haruhiko, Takakura, Nobuyuki
• Format: Article
• Language: English
• Subjects: angiogenesis; Animals; Antigens, CD - metabolism; Cadherins - metabolism; Cell Communication - drug effects; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Proliferation - drug effects; drug delivery; Drug Delivery Systems; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial Cells - ultrastructure; LPA; LPA4; Lysophospholipids - pharmacology; Mice; Neoplasms - blood supply; Neoplasms - drug therapy; Neoplasms - ultrastructure; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Receptors, Lysophosphatidic Acid - metabolism; Signal Transduction - drug effects; VE-cadherin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.07.080

Vascular normalization in tumors may improve drug delivery and anti-tumor immunity. Angiogenesis inhibitors induce hypoxia, which may facilitate malignant progression; therefore, we investigated other methods to promote vascular maturation. Here, we show that lysophosphatidic acid (LPA) enhances blood flow by promoting fine vascular networks, thereby improving vascular permeability and suppressing tumor growth when combined with anti-cancer drug treatment. Six different G protein-coupled receptors have been identified as LPA receptors (LPA1–6). In studies using mutant mice, we found that LPA4 is involved in vascular network formation. LPA4 activation induces circumferential actin bundling beneath the cell membrane and enhances linear adherens junction formation by VE-cadherin in endothelial cells. Therefore, we conclude that activation of LPA4 is a promising approach for vascular regulation. [Display omitted] •Lysophosphatidic acid (LPA) promotes fine vascular network formation in tumors•LPA improves drug delivery into tumors•Vascular network formation by LPA is induced by LPA4 through Gi or Gα12/13 activation•LPA promotes membrane localization of VE-cadherin in endothelial cells Takara et al. find that lysophosphatidic acid (LPA) promotes fine capillary network formation and improves drug delivery in tumors. LPA controls localization of VE-cadherin in endothelial cells through LPA receptor 4 (LPA4) signaling.