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

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

Author information

1
Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
2
Weill Medical College of Cornell University, New York, New York.
3
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Pathology and, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
6
Weill Cornell Medical College, Department of Pathology, Division of Neuropathology, New York, New York.
7
Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, New York.
8
Weill Cornell Medical College, New York, New York.
9
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. bromberj@mskcc.org jpgreenf@med.cornell.edu.
10
Department of Neurological Surgery, Weill Cornell Medical College, New York, New York. bromberj@mskcc.org jpgreenf@med.cornell.edu.

Abstract

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.

PMID:
28039266
PMCID:
PMC5769921
DOI:
10.1158/1078-0432.CCR-16-1508
[Indexed for MEDLINE]
Free PMC Article

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