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

Int J Cancer. 2017 Mar 15;140(6):1370-1383. doi: 10.1002/ijc.30538.


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.

Keywords: E-selectin; IL-1β; mo-MDSCs; premetastatic niche; tumor cell arrest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion
  • Cell Movement
  • Coculture Techniques
  • E-Selectin / biosynthesis*
  • E-Selectin / genetics
  • Endothelium, Vascular / pathology
  • Gene Expression Regulation, Neoplastic / immunology
  • Gene Knockdown Techniques
  • Interleukin-1beta / physiology*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Macrophages / metabolism
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / secondary*
  • Mice
  • Mice, Inbred C57BL
  • Monocyte Chemoattractant Proteins / genetics
  • Monocyte Chemoattractant Proteins / physiology
  • Monocytes / physiology*
  • Myeloid-Derived Suppressor Cells / classification
  • Myeloid-Derived Suppressor Cells / physiology*
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • Neoplastic Cells, Circulating*
  • Organ Specificity
  • Stem Cell Niche*
  • Tumor Cells, Cultured
  • Tumor Microenvironment*


  • Ccl12 protein, mouse
  • E-Selectin
  • Interleukin-1beta
  • Monocyte Chemoattractant Proteins
  • Neoplasm Proteins