Chen Peiwen, Zuo Hao, Xiong Hu, Kolar Matthew J, Chu Qian, Saghatelian Alan, Siegwart Daniel J, Wan Yihong
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):580-585. doi: 10.1073/pnas.1614035114. Epub 2017 Jan 3.
Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor-macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor-macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment.
巨噬细胞是肿瘤微环境中重要的免疫细胞，对癌症转移具有强大作用。然而，肿瘤与巨噬细胞之间通讯的信号和受体仍不清楚。在此，我们表明G蛋白偶联受体132（Gpr132）作为酸性肿瘤环境中乳酸水平升高的关键巨噬细胞传感器，在乳腺癌转移过程中介导癌细胞与巨噬细胞之间的相互作用。乳酸激活巨噬细胞Gpr132以促进交替激活的巨噬细胞（M2）样表型，进而促进癌细胞的黏附、迁移和侵袭。因此，Gpr132缺失可减少M2巨噬细胞，并阻碍小鼠乳腺癌肺转移。临床上，Gpr132表达与乳腺癌患者的M2巨噬细胞、转移及不良预后呈正相关。这些发现揭示了乳酸-Gpr132轴通过刺激肿瘤-巨噬细胞相互作用而成为乳腺癌转移的驱动因素，并揭示了乳腺癌治疗潜在的新治疗靶点。
