Cancer-associated adipocytes promote the invasion and metastasis in breast cancer through LIF/CXCLs positive feedback loop

• Published in: International journal of biological sciences 2022-01, Vol.18 (4), p.1363-1380
• Main Authors: Zhou, Chong, He, Xi, Tong, Chang, Li, Honghui, Xie, Caifeng, Wu, Yudong, Wang, Lieliang, Yan, Xiaohua, Luo, Daya, Tang, Yunpeng, Cheng, Zhongman, Xiong, Xiangyang
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipocytes - metabolism; Adipose tissue; Antibodies; Body fat; Breast cancer; Breast Neoplasms - metabolism; Cell adhesion & migration; Cell culture; Chemokine receptors; Crosstalk; CXCR2 protein; Cytokines; Feedback; Feedback loops; Female; Gene expression; Glutamic acid; Humans; Inflammation; Leucine; Leukemia; Leukemia inhibitory factor; Leukemia Inhibitory Factor - genetics; Leukemia Inhibitory Factor - metabolism; Lung cancer; Lung Neoplasms - metabolism; Lungs; Metastases; Metastasis; NF-κB protein; Pore size; Positive feedback; Research Paper; Signal transduction; Signaling; Stat3 protein; Tumor cells; Tumor necrosis factor-TNF; Tumors
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.65227

Cancer-associated adipocytes (CAAs), which are adipocytes transformed by cancer cells, are of great importance in promoting the progression of breast cancer. However, the underlying mechanisms involved in the crosstalk between cancer cells and adipocytes are still unknown. Here we report that CAAs and breast cancer cells communicate with each other by secreting the cytokines leukemia inhibitory factor (LIF) and C-X-C subfamily chemokines (CXCLs), respectively. LIF is a pro-inflammatory cytokine secreted by CAAs, which promotes migration and invasion of breast cancer cells via the Stat3 signaling pathway. The activation of Stat3 induced the secretion of glutamic acid-leucine-arginine (ELR) motif CXCLs (CXCL1, CXCL2, CXCL3 and CXCL8) in tumor cells. Interestingly, CXCLs in turn activated the ERK1/2/NF-κB/Stat3 signaling cascade to promote the expression of LIF in CAAs. In clinical breast cancer pathology samples, the up-regulation of LIF in paracancerous adipose tissue was positively correlated with the activation of Stat3 in breast cancer. Furthermore, we verified that adipocytes enhanced lung metastasis of breast cancer cells, and the combination of EC330 (targeting LIF) and SB225002 (targeting C-X-C motility chemokine receptor 2 (CXCR2)) significantly reduced lung metastasis of breast cancer cells . Our findings reveal that the interaction of adipocytes with breast cancer cells depends on a positive feedback loop between the cytokines LIF and CXCLs, which promotes breast cancer invasion and metastasis.