Controlling the Phenotype of Tumor-Infiltrating Macrophages via the PHD-HIF Axis Inhibits Tumor Growth in a Mouse Model

被引：21

作者：

Nishide, Shunji ^{[1
,2
]}

Matsunaga, Shinji ^{[1
]}

Shiota, Masayuki ^{[3
]}

Yamaguchi, Takehiro ^{[1
]}

Kitajima, Shojiro ^{[1
]}

Maekawa, Yoichi ^{[4
,5
]}

Takeda, Norihiko ^{[6
]}

Tomura, Michio ^{[7
]}

Uchida, Junji ^{[2
]}

Miura, Katsuyuki ^{[8
]}

Nakatani, Tatsuya ^{[2
]}

Tomita, Shuhei ^{[1
]}

机构：

[1] Osaka City Univ, Grad Sch Med, Dept Pharmacol, Osaka 5458585, Japan

[2] Osaka City Univ, Grad Sch Med, Dept Urol, Osaka 5458585, Japan

[3] Osaka City Univ, Grad Sch Med, Div Res Support Platform, Osaka 5458585, Japan

[4] Gifu Univ, Grad Sch Med, Dept Parasitol & Infect Dis, Gifu 5011194, Japan

[5] Gifu Univ, Ctr Highly Adv Integrat Nano & Life Sci, Domain Integrated Life Syst, Gifu 5011193, Japan

[6] Univ Tokyo, Grad Sch Med, Dept Cardiovasc Med, Tokyo 1138655, Japan

[7] Osaka Ohtani Univ, Immunol Lab, Fac Pharm, Osaka 5848540, Japan

[8] Osaka City Univ, Grad Sch Med, Dept Appl Pharmacol & Therapeut, Osaka 5458585, Japan

来源：

ISCIENCE | 2019年 / 19卷

关键词：

VESSEL NORMALIZATION; ROXADUSTAT FG-4592; T-CELLS; HYPOXIA; ANGIOGENESIS; INFLAMMATION; METASTASIS; ANEMIA; IMPACT;

D O I：

10.1016/j.isci.2019.08.033

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6C(lo) subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6C(neg) macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy.

引用

页码：940 / +

页数：35

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