Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G+Ly6C+ granulocytes

Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21248-55. doi: 10.1073/pnas.1015855107. Epub 2010 Nov 16.


Priming of the organ-specific premetastatic sites is thought to be an important yet incompletely understood step during metastasis. In this study, we show that the metastatic tumors we examined overexpress granulocyte-colony stimulating factor (G-CSF), which expands and mobilizes Ly6G+Ly6C+ granulocytes and facilitates their subsequent homing at distant organs even before the arrival of tumor cells. Moreover, G-CSF-mobilized Ly6G+Ly6C+ cells produce the Bv8 protein, which has been implicated in angiogenesis and mobilization of myeloid cells. Anti-G-CSF or anti-Bv8 antibodies significantly reduced lung metastasis. Transplantation of Bv8 null fetal liver cells into lethally irradiated hosts also reduced metastasis. We identified an unexpected role for Bv8: the ability to stimulate tumor cell migration through activation of one of the Bv8 receptors, prokineticin receptor (PKR)-1. Finally, we show that administration of recombinant G-CSF is sufficient to increase the numbers of Ly6G+Ly6C+ cells in organ-specific metastatic sites and results in enhanced metastatic ability of several tumors.

MeSH terms

  • Animals
  • Antigens, Ly / immunology*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Female
  • Gene Expression Profiling
  • Granulocyte Colony-Stimulating Factor / genetics
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Granulocytes / cytology
  • Granulocytes / drug effects*
  • Granulocytes / immunology*
  • Lung Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, SCID
  • Microarray Analysis
  • Neoplasm Metastasis*
  • Neoplasm Transplantation
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology


  • Antigens, Ly
  • Antineoplastic Agents
  • Ly-6C antigen, mouse
  • Ly6G antigen, mouse
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor