Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
J Cell Physiol. 2021 Jun;236(6):4669-4680. doi: 10.1002/jcp.30189. Epub 2021 Jan 9.
Triple-negative breast cancer (TNBC) exhibits a higher level of glycolytic capacity and are commonly associated with an inflammatory microenvironment, but the regulatory mechanism and metabolic crosstalk between the tumor and tumor microenvironment (TME) are largely unresolved. Here, we show that glucose transporter 3 (GLUT3) is particularly elevated in TNBC and associated with metastatic progression and poor prognosis in breast cancer patients. Expression of GLUT3 is crucial for promoting the epithelial-to-mesenchymal transition and enhancing invasiveness and distant metastasis of TNBC cells. Notably, GLUT3 is correlated with inflammatory gene expressions and is associated with M1 tumor-associated macrophages (TAMs), at least in part by C-X-C Motif Chemokine Ligand 8 (CXCL8). We found that expression of GLUT3 regulates CXCL8 production in TNBC cells. Secretion of CXCL8 participates in GLUT3-overexpressing TNBC cells-elicited activation of inflammatory TAMs, which further enhances GLUT3 expression and mobility of TNBC cells. Our findings demonstrate that aerobic glycolysis in TNBC not only promotes aggressiveness of tumor cells but also initiates a positive regulatory loop for enhancing tumor progression by modulating the inflammatory TME.
三阴性乳腺癌（TNBC）表现出更高水平的糖酵解能力，通常与炎症微环境相关，但肿瘤和肿瘤微环境（TME）之间的调节机制和代谢串扰在很大程度上仍未得到解决。在这里，我们表明葡萄糖转运蛋白 3（GLUT3）在 TNBC 中特别升高，并与乳腺癌患者的转移进展和预后不良相关。GLUT3 的表达对于促进上皮-间充质转化以及增强 TNBC 细胞的侵袭性和远处转移至关重要。值得注意的是，GLUT3 与炎症基因表达相关，并与 M1 肿瘤相关巨噬细胞（TAMs）相关，至少部分通过 C-X-C 基序趋化因子配体 8（CXCL8）。我们发现 GLUT3 的表达调节 TNBC 细胞中 CXCL8 的产生。CXCL8 的分泌参与 GLUT3 过表达的 TNBC 细胞诱导的炎症性 TAMs 的激活，这进一步增强了 TNBC 细胞的 GLUT3 表达和迁移能力。我们的研究结果表明，TNBC 中的有氧糖酵解不仅促进肿瘤细胞的侵袭性，而且通过调节炎症性 TME 引发增强肿瘤进展的正反馈循环。
