title: Malignant Astrocytic Tumor Progression Potentiated by JAK-mediated Recruitment of Myeloid Cells.
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 progressionin vivoand prolongs survival in a murine glioma model.Clin Cancer Res; 23(12); 3109-19. ©2016 AACR.
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Rajappa
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: William S
authors.initials: WS
authors.lastname: Cobb
authors.affiliation: Weill Medical College of Cornell University, New York, New York.
authors.forename: Emma
authors.initials: E
authors.lastname: Vartanian
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laura
authors.initials: L
authors.lastname: Daly
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Hoffman
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jane
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Weill Medical College of Cornell University, New York, New York.
authors.forename: Beiyi
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Rachel
authors.initials: R
authors.lastname: Yanowitch
authors.affiliation: Weill Medical College of Cornell University, New York, New York.
authors.forename: Kunal
authors.initials: K
authors.lastname: Garg
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Babacar
authors.initials: B
authors.lastname: Cisse
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sara
authors.initials: S
authors.lastname: Haddock
authors.affiliation: Department of Pathology and, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Jason
authors.initials: J
authors.lastname: Huse
authors.affiliation: Weill Cornell Medical College, Department of Pathology, Division of Neuropathology, New York, New York.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pisapia
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, Cell and Developmental Biology, Weill Cornell Medical College, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: David C
authors.initials: DC
authors.lastname: Lyden
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. bromberj@mskcc.org jpgreenf@med.cornell.edu.|Weill Cornell Medical College, New York, New York.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Bromberg
authors.affiliation: Department of Neurological Surgery, Weill Cornell Medical College, New York, New York. bromberj@mskcc.org jpgreenf@med.cornell.edu.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D039481:CD11b Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C545606:AZD 1480; D039481:CD11b Antigen; C509295:ITGAM protein, human; D011720:Pyrazoles; D011743:Pyrimidines; D053613:Janus Kinase 1