Huang, YujieRajappa, PrajwalHu, WenhuoHoffman, CaitlinCisse, BabacarKim, Joon-HyungGorge, EmilieYanowitch, RachelCope, WilliamVartanian, EmmaXu, RaymondZhang, TuoPisapia, DavidXiang, JennyHuse, JasonMatei, IrinaPeinado Selgas, HectorBromberg, JacquelineHolland, EricDing, Bi-SenRafii, ShahinLyden, DavidGreenfield, Jeffrey2019-09-302019-09-302017-05-01J Clin Invest. 2017 ;127(5):1826-1838.0021-9738http://hdl.handle.net/20.500.12105/8388Tumors are capable of coopting hematopoietic cells to create a suitable microenvironment to support malignant growth. Here, we have demonstrated that upregulation of kinase insert domain receptor (KDR), also known as VEGFR2, in a myeloid cell sublineage is necessary for malignant progression of gliomas in transgenic murine models and is associated with high-grade tumors in patients. KDR expression increased in myeloid cells as myeloid-derived suppressor cells (MDSCs) accumulated, which was associated with the transformation and progression of low-grade fibrillary astrocytoma to high-grade anaplastic gliomas. KDR deficiency in murine BM-derived cells (BMDCs) suppressed the differentiation of myeloid lineages and reduced granulocytic/monocytic populations. The depletion of myeloid-derived KDR compromised its proangiogenic function, which inhibited the angiogenic switch necessary for malignant progression of low-grade to high-grade tumors. We also identified inhibitor of DNA binding protein 2 (ID2) as a key upstream regulator of KDR activation during myeloid differentiation. Deficiency of ID2 in BMDCs led to downregulation of KDR, suppression of proangiogenic myeloid cells, and prevention of low-grade to high-grade transition. Tumor-secreted TGF-β and granulocyte-macrophage CSF (GM-CSF) enhanced the KDR/ID2 signaling axis in BMDCs. Our results suggest that modulation of KDR/ID2 signaling may restrict tumor-associated myeloid cells and could potentially be a therapeutic strategy for preventing transformation of premalignant gliomas.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/AnimalsCell Line, TumorGranulocyte-Macrophage Colony-Stimulating FactorHumansInhibitor of Differentiation Protein 2MiceMice, TransgenicNeoplasm ProteinsSignal TransductionTransforming Growth Factor betaVascular Endothelial Growth Factor Receptor-2Bone Marrow CellsGliomaMyeloid CellsNeovascularization, PathologicAtribución-NoComercial-CompartirIgual 4.0 Internacional2839425912751826-183810.1172/JCI864431558-8238The Journal of clinical investigationopen access