Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis
Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis
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DOI：
10.1073/pnas.1614035114
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发表时间：
2017-01-17
影响因子：
11.1
通讯作者：
Wan, Yihong
中科院分区：
文献类型：
--
作者：
Chen, Peiwen;Zuo, Hao;Wan, Yihong
巨噬细胞是肿瘤微环境中重要的免疫细胞，在肿瘤转移中发挥重要作用。然而，肿瘤-巨噬细胞通讯的信号和接收器仍然是个谜。在这里，我们发现G蛋白偶联受体132(GPR132)是酸性肿瘤环境中乳酸升高的关键巨噬细胞感受器，在乳腺癌转移过程中介导癌细胞和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缺失减少了M2巨噬细胞，并阻止了小鼠乳腺癌的肺转移。临床上，GPR132的表达与乳腺癌患者的M2巨噬细胞、转移及预后不良呈正相关。这些发现揭示了乳酸-GPR132轴通过刺激肿瘤-巨噬细胞的相互作用而作为乳腺癌转移的驱动因素，并揭示了乳腺癌治疗的潜在治疗靶点。
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.