Lactoferrin deficiency induces a pro-metastatic tumor microenvironment through recruiting myeloid-derived suppressor cells in mice

• Published in: Oncogene 2020-01, Vol.39 (1), p.122-135
• Main Authors: Wei, Lingyu, Zhang, Xuemei, Wang, Jia, Ye, Qiurong, Zheng, Xiang, Peng, Qiu, Zheng, Ying, Liu, Peishan, Zhang, Xiaoyue, Li, Zhengshuo, Liu, Can, Yan, Qun, Li, Guiyuan, Ma, Jian
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/31; 38/77; 38/91; 631/250/2504; 631/67/327; 64/110; 64/60; 96/106; 96/2; Animals; Antitumor agents; Apoptosis; Apoptosis - genetics; B cells; Cancer; Cell Biology; Cell Differentiation - genetics; Cell Line, Tumor; Disease Models, Animal; Gene Expression Regulation, Neoplastic - genetics; Heterografts; Human Genetics; Humans; Immune system; Immunity, Innate - genetics; Inflammation; Innate immunity; Internal Medicine; Lactoferrin; Lactoferrin - deficiency; Lactoferrin - genetics; Lactoferrin - pharmacology; Lactoferrins; Lung - metabolism; Lung - pathology; Lungs; Medicine; Medicine & Public Health; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - pathology; Metastases; Metastasis; Mice; Mice, Knockout; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Nasopharyngeal carcinoma; Neoplasm Metastasis; Oncology; Phenotypes; Signal Transduction - genetics; Suppressor cells; Throat cancer; TLR9 protein; Toll-Like Receptor 9 - agonists; Toll-Like Receptor 9 - genetics; Toll-like receptors; Tumor microenvironment; Tumor Microenvironment - genetics
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0970-8

Lactoferrin, an innate immunity molecule, is involved in anti-inflammatory, anti-microbial, and anti-tumor activities. We previously reported that lactoferrin is downregulated in specimens of nasopharyngeal carcinoma and negatively associated with tumor progression and metastasis of patients with nasopharyngeal carcinoma. However, the relationship between lactoferrin and the pro-metastatic microenvironment has not been reported yet. Here, by using the lactoferrin knockout mouse, we found that lactoferrin deficiency facilitated melanoma cells metastasizing to lungs, through recruiting myeloid-derived suppressor cells (MDSCs) in the lungs. Mechanistic studies showed that in the lung microenvironment of the lactoferrin knockout mice, the TLR9 signaling was the most repressed signaling. Lactoferrin can induce MDSCs differentiation and apoptosis, as well as upregulate TLR9 expression. TLR9 agonist or lactoferrin treatment can rescue this phenotype in the tumor metastasis mouse model. Our results suggest a protective role of lactoferrin in cancer metastasis, along with a deficiency in certain components of the innate immune system, may lead to a pro-metastatic tumor microenvironment.