Purpose: Secreted cytokines play a significant role in modulating cancer metastatic microenvironment, especially for tumor associated macrophages (TAMs). The current study aimed to determine the significance of TAMs-secreted CXCL1 in regulating cancer metastasis and its underlying mechanisms. Experimental Design: Cytokine array was utilized to screen the highest chemokine secreted from TAMs. In vivo immunohistochemistry assay and in vitro wound healing or transwell experiments were carried out to demonstrate the metastatic-promoting effects of TAMs/CXCL1. QPCR profile screening was used to identify CXCL1 targeting metastasis-related gene. In vivo luciferase imaging experiments were designed to confirm the therapeutic significance of CXCL1 silencing on breast cancer metastasis. The clinical significance of CXCL1 was analyzed by human tissue microarray and bioinformatic analysis. Results: CXCL1 was validated as the highest secreted protein released from TAMs, and TAMs-derived CXCL1 could promote breast cancer migration and invasion ability, as well as epithelial-mesenchymal transition (EMT) process. QPCR screening validated SOX4 as the most responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 activates SOX4 transcription via NF-κB pathway. CXCL1 silencing in TAMs resulted in a significant reduction in breast cancer growth and metastatic burden. Clinical investigation suggests that high CXCL1 expression was significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Conclusions: TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/sox4 activation, and CAV1 based therapy might become a novel strategy for breast cancer metastasis prevention.
Citation Format: Zhiyu Wang, Neng Wang, Weiping Liu, Yifeng Zheng, Shengqi Wang. Tumor-associated macrophages-secreted CXCL1 promotes breast cancer metastasis via activating NF-κB/SOX4 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1104.