Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells

Clin Cancer Res. 2017 Jun 15;23(12):3109-3119. doi: 10.1158/1078-0432.CCR-16-1508. Epub 2016 Dec 30.


Purpose: While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow-derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.Experimental Design: We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b+/GR1+ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).Results: CD11b+ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b+/GR1+ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b+ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.Conclusions: We demonstrate that impaired recruitment of CD11b+ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression in vivo and prolongs survival in a murine glioma model. Clin Cancer Res; 23(12); 3109-19. ©2016 AACR.

MeSH terms

  • Animals
  • Astrocytoma / blood
  • Astrocytoma / drug therapy*
  • Astrocytoma / genetics
  • Astrocytoma / pathology
  • CD11b Antigen / antagonists & inhibitors
  • CD11b Antigen / immunology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / genetics*
  • Male
  • Mice
  • Myeloid Cells / drug effects
  • Myeloid Cells / pathology
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Pyrazoles / administration & dosage*
  • Pyrimidines / administration & dosage*
  • Tumor Microenvironment / drug effects


  • AZD 1480
  • CD11b Antigen
  • ITGAM protein, human
  • Pyrazoles
  • Pyrimidines
  • Janus Kinase 1