Cytokines constitute a family of proteins that modulate the immune system and are secreted by many cells. CXCL12, along with its receptor CXCR4, are essential players in numerous processes. Dysregulation of their function underlie the mechanism(s) of several pathologies, including malignancies. Here, we demonstrate an unexpected effect of the cytokine and its receptor: In both cells and animal models, CXCL12 restricts tumorigenicity of the human glioblastoma cells U87-MG and U-118, and of a cell line derived from PyMT mouse breast cancer. Overexpression of CXCL12 inhibits activation of the oncogene Ras which results in downregulation of its proliferative signals, such as reduced phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2), inhibition of c-Myc expression, and subsequent inhibition of cell cycle. Furthermore, CXCL12 induces downregulation of the growth differentiation factor 15 (GDF15), insulin-like growth factor-binding protein 6 (IGFBP6), and matrix metalloproteinase-3 (MMP3), which are implicated in sending metastases. Indeed, monitoring cell migration in vitro and generation of metastases in mice demonstrate that CXCL12 slows the migration of U87-MG and PyMT cells. Remarkably, overexpression of CXCL12 also downregulates the cell surface immune checkpoint protein programmed cell death-ligand 1 (PD-L1), resulting in recruitment of cytotoxic CD8 T cells into xenografts accompanied by their shrinkage. Overall, CXCL12 inhibits tumor growth through several distinct mechanisms: inhibition of cell cycle and migration, as well as impairment of immune checkpoint, thereby stimulating a strong host’s immune response. The mechanism(s) that renders CXCL12 a tumor-promoting factor in certain cells and a suppressor in others has remained elusive.

中文翻译：

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CXCL12 通过抑制 Ras、ERK1/2、c-Myc 和免疫检查点 PD-L1 通路来限制肿瘤生长


细胞因子构成一个调节免疫系统的蛋白质家族，由许多细胞分泌。CXCL12 及其受体 CXCR4 是许多过程中的重要参与者。其功能失调是多种病理学（包括恶性肿瘤）机制的基础。在这里，我们证明了细胞因子及其受体的意外作用：在细胞和动物模型中，CXCL12 限制了人胶质母细胞瘤细胞 U87-MG 和 U-118 以及 PyMT 小鼠乳腺癌来源的细胞系的致瘤性。CXCL12 过表达抑制癌基因 Ras 的激活，从而导致其增殖信号下调，例如细胞外信号调节激酶 1/2 （ERK1/2） 的磷酸化降低、c-Myc 表达抑制以及随后的细胞周期抑制。此外，CXCL12 诱导生长分化因子 15 （GDF15） 、胰岛素样生长因子结合蛋白 6 （IGFBP6） 和基质金属蛋白酶-3 （MMP3） 的下调，这些物质与发送转移有关。事实上，体外监测细胞迁移和小鼠转移的产生表明 CXCL12 减缓了 U87-MG 和 PyMT 细胞的迁移。值得注意的是，CXCL12 的过表达还下调了细胞表面免疫检查点蛋白程序性细胞死亡配体 1 （PD-L1），导致细胞毒性 CD8 T 细胞募集到异种移植物中并伴有收缩。总体而言，CXCL12 通过几种不同的机制抑制肿瘤生长：抑制细胞周期和迁移，以及损害免疫检查点，从而刺激强宿主的免疫反应。使 CXCL12 在某些细胞中成为肿瘤促进因子而在其他细胞中成为抑制因子的机制仍然难以捉摸。