title: Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1β-mediated increase in E-selectin expression.
abstract: The tumor premetastatic niche initiated by primary tumors is constructed by multiple molecular factors and cellular components and provides permissive condition that allows circulating tumor cells to successfully metastasize. Myeloid-derived suppressor cells (MDSCs), a population of immature cells in pathological conditions, play a critical role in the formation of the premetastatic niche. However, few researches are focused on the function of monocytic MDSCs (mo-MDSCs), a subtype of MDSCs, in the construction of the niche. Here, we show that the number of mo-MDSCs is significantly increased in the premetastatic lungs of tumor-bearing mice, thus promoting tumor cell arrest and metastasis. Before the arrival of tumor cells, the lung-recruited mo-MDSCs produced IL-1β, thereby increasing E-selectin expression and promoting tumor cell arrest on endothelial cells. Depletion of mo-MDSCs in the premetastatic lungs decreased IL-1β production, resulting in reduced E-selectin expression. In addition, compared with alveolar macrophages and interstitial macrophages, mo-MDSCs were the major source of IL-1β expression in the premetastatic lungs. Cytokine array analyses and transwell experiments revealed that CCL12 recruits mo-MDSCs to premetastatic lungs. CCL12 knockdown in tumor-bearing mice significantly decreased mo-MDSC infiltration into the premetastatic lungs, leading to reduced E-selectin expression. Overall, the permissive conditions produced by the infiltrated mo-MDSCs correlated with increased tumor cell arrest and metastasis. These results reveal a novel role of mo-MDSCs in constructing the premetastatic niche. Thus, inhibition of mo-MDSCs infiltration may change the premetastatic niche to normal condition and attenuate tumor metastasis.
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Shi
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Juechao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Han
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Huihan
authors.initials: H
authors.lastname: Li
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Mingshu
authors.initials: M
authors.lastname: Xie
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Wenguang
authors.initials: W
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ba
authors.affiliation: The Key Laboratory of Molecular Epigenetics of MOE, Institute of Genetics and Cytology, School of Life Sciences, Northeast Normal University, Changchun, Jilin, China.
authors.forename: Xianlu
authors.initials: X
authors.lastname: Zeng
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D018920:Coculture Techniques; D019040:E-Selectin / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D055785:Gene Knockdown Techniques; D053583:Interleukin-1beta / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008264:Macrophages / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000502:physiology; D009000:Monocytes / Q000502:physiology*; D000072737:Myeloid-Derived Suppressor Cells / Q000145:classification / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009360:Neoplastic Cells, Circulating; D009928:Organ Specificity; D055153:Stem Cell Niche; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: C491224:Ccl12 protein, mouse; D019040:E-Selectin; D053583:Interleukin-1beta; D018945:Monocyte Chemoattractant Proteins; D009363:Neoplasm Proteins
keywords: E-selectin; IL-1β; mo-MDSCs; premetastatic niche; tumor cell arrest