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oai:repisalud.isciii.es:20.500.12105/83882024-11-30T00:39:59Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Huang, Yujie author Rajappa, Prajwal author Hu, Wenhuo author Hoffman, Caitlin author Cisse, Babacar author Kim, Joon-Hyung author Gorge, Emilie author Yanowitch, Rachel author Cope, William author Vartanian, Emma author Xu, Raymond author Zhang, Tuo author Pisapia, David author Xiang, Jenny author Huse, Jason author Matei, Irina author Peinado Selgas, Hector author Bromberg, Jacqueline author Holland, Eric author Ding, Bi-Sen author Rafii, Shahin author Lyden, David author Greenfield, Jeffrey author 2017-05-01 Tumors 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. J Clin Invest. 2017 ;127(5):1826-1838. 10.1172/JCI86443 1558-8238 0021-9738 The Journal of clinical investigation 28394259 http://hdl.handle.net/20.500.12105/8388 A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma