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

Oncogene volume 39, pages 122–135 (2020)Cite this article

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Abstract

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.

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Acknowledgements

This work was funded by National Natural Science Foundation of China (81672889, 81874170, and 81472694), China 111 Project (111-2-12), Hunan Province Science and Technology Project (2016JC2035), Open Research Fund Program of Key Laboratory of Translational Radiation Oncology, Hunan Province (2015TP1009), Independent Exploration and Innovation Project of Central South University (178301003), and National College Students’ Innovation and Entrepreneurship Training Program of China (201810533376, GS201910533237). We thank Professors Wen Zhou and Ya Cao for providing reagents; Professor Penghui Zhou providing key suggestions.

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  1. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Third Xiangya Hospital, Central South University, Changsha, China

    Lingyu Wei, Xuemei Zhang, Guiyuan Li & Jian Ma

  2. Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, China

    Lingyu Wei, Xuemei Zhang, Jia Wang, Qiurong Ye, Xiang Zheng, Qiu Peng, Peishan Liu, Xiaoyue Zhang, Zhengshuo Li, Can Liu, Guiyuan Li & Jian Ma

  3. Key Laboratory of Carcinogenesis of Ministry of Health, Changsha, China

    Lingyu Wei, Guiyuan Li & Jian Ma

  4. Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Changsha, China

    Lingyu Wei, Guiyuan Li & Jian Ma

  5. Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Lingyu Wei, Xuemei Zhang & Jian Ma

  6. Center for Medical Research, Second Xiangya Hospital, Central South University, Changsha, China

    Ying Zheng

  7. Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China

    Qun Yan

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  1. Lingyu Wei
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Contributions

Conception and design: LW and JM. Development of methodology: LW., XZ, JW, QY, and YZ. Acquisition of data: XZ, QP, PL, XZ, ZL, CL, and QY. Analysis and interpretation of data: LW, JW, XZ, and JM. Writing: LW and JM. Study supervision: GL and JM.

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Correspondence to Jian Ma.

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Wei, L., Zhang, X., Wang, J. et al. Lactoferrin deficiency induces a pro-metastatic tumor microenvironment through recruiting myeloid-derived suppressor cells in mice. Oncogene 39, 122–135 (2020). https://doi.org/10.1038/s41388-019-0970-8

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