2026-05-20T23:49:37Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/83882024-11-30T00:39:59Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
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
funder
Elizabeths Hope
funder
Starr Foundation
funder
Paduano Foundation
funder
Champalimaud Foundation
funder
Malcolm Hewitt Wiener Foundation
funder
POETIC Foundation
funder
Sohn Foundation
funder
Hartwell Foundation
funder
Children's Cancer and Blood Foundation
2019-09-30T09:36:34Z
2019-09-30T09:36:34Z
2017-05-01
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
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.
eng
A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma
journal article
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