| RRC ID |
66959
|
| 著者 |
Eino D, Tsukada Y, Naito H, Kanemura Y, Iba T, Wakabayashi T, Muramatsu F, Kidoya H, Arita H, Kagawa N, Fujimoto Y, Takara K, Kishima H, Takakura N.
|
| タイトル |
LPA4-Mediated Vascular Network Formation Increases the Efficacy of Anti-PD-1 Therapy against Brain Tumors.
|
| ジャーナル |
Cancer Res
|
| Abstract |
: The structure and function of tumor blood vessels profoundly affects the tumor microenvironment. Signals mediated through the lysophosphatidic acid receptor 4 (LPA4) promote vascular network formation to restore normal vascular barrier function in subcutaneous tumors and thus improve drug delivery. However, the characteristics of the vasculature vary by organ and tumor types, and how drug delivery and leukocyte trafficking are affected by modification of vascular function by LPA in different cancers is unclear. Here, we show that LPA4 activation promotes the formation of fine vascular structures in brain tumors. RhoA/ROCK signaling contributed to LPA-induced endothelial cell-cell adhesion, and RhoA/ROCK activity following LPA4 stimulation regulated expression of VCAM-1. This resulted in increased lymphocyte infiltration into the tumor. LPA improved delivery of exogenous IgG into brain tumors and enhanced the anticancer effect of anti-programmed cell death-1 antibody therapy. These results indicate the effects of LPA on vascular structure and function apply not only to chemotherapy but also to immunotherapy. SIGNIFICANCE: These findings demonstrate that lysophosphatidic acid, a lipid mediator, promotes development of a fine capillary network in brain tumors by inducing tightening of endothelial cell-to-cell adhesion, facilitating improved drug delivery, and lymphocyte penetration.
|
| 巻・号 |
78(23)
|
| ページ |
6607-6620
|
| 公開日 |
2018-12-1
|
| DOI |
10.1158/0008-5472.CAN-18-0498
|
| PII |
0008-5472.CAN-18-0498
|
| PMID |
30301839
|
| MeSH |
Animals
Antineoplastic Agents, Immunological / pharmacology*
Brain Neoplasms / drug therapy
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism*
Brain Neoplasms / pathology
Cell Line, Tumor
Disease Models, Animal
Endothelial Cells / metabolism
Female
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Mice
Mice, Knockout
NF-kappa B / metabolism
Neovascularization, Pathologic / drug therapy
Neovascularization, Pathologic / genetics*
Programmed Cell Death 1 Receptor / antagonists & inhibitors*
RNA, Small Interfering / genetics
Receptors, Purinergic / genetics*
Receptors, Purinergic / metabolism
Signal Transduction
Treatment Outcome
Vascular Cell Adhesion Molecule-1 / metabolism
Xenograft Model Antitumor Assays
rho-Associated Kinases / metabolism
rhoA GTP-Binding Protein / metabolism
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
LLC(RCB0558)
OP9(RCB1124) |
