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

TitleMalignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsRajappa P, Cobb WS, Vartanian E, Huang Y, Daly L, Hoffman C, Zhang J, Shen B, Yanowitch R, Garg K, Cisse B, Haddock S, Huse J, Pisapia DJ, Chan TA, Lyden DC, Bromberg JF, Greenfield JP
JournalClin Cancer Res
Volume23
Issue12
Pagination3109-3119
Date Published2017 Jun 15
ISSN1557-3265
KeywordsAnimals, Astrocytoma, CD11b Antigen, Cell Line, Tumor, Cell Proliferation, Disease Models, Animal, Disease Progression, Female, Humans, Janus Kinase 1, Male, Mice, Myeloid Cells, Neovascularization, Pathologic, Pyrazoles, Pyrimidines, Tumor Microenvironment
Abstract

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. 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). 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. We demonstrate that impaired recruitment of CD11b myeloid cells with a JAK1/2 inhibitor inhibits glioma progression and prolongs survival in a murine glioma model. .

DOI10.1158/1078-0432.CCR-16-1508
Alternate JournalClin Cancer Res
PubMed ID28039266
PubMed Central IDPMC5769921
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States