title: A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.
abstract: 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.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Huang
authors.forename: Prajwal
authors.initials: P
authors.lastname: Rajappa
authors.forename: Wenhuo
authors.initials: W
authors.lastname: Hu
authors.forename: Caitlin
authors.initials: C
authors.lastname: Hoffman
authors.forename: Babacar
authors.initials: B
authors.lastname: Cisse
authors.forename: Joon-Hyung
authors.initials: JH
authors.lastname: Kim
authors.forename: Emilie
authors.initials: E
authors.lastname: Gorge
authors.forename: Rachel
authors.initials: R
authors.lastname: Yanowitch
authors.forename: William
authors.initials: W
authors.lastname: Cope
authors.forename: Emma
authors.initials: E
authors.lastname: Vartanian
authors.forename: Raymond
authors.initials: R
authors.lastname: Xu
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Pisapia
authors.forename: Jenny
authors.initials: J
authors.lastname: Xiang
authors.forename: Jason
authors.initials: J
authors.lastname: Huse
authors.forename: Irina
authors.initials: I
authors.lastname: Matei
authors.forename: Hector
authors.initials: H
authors.lastname: Peinado
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
authors.forename: Eric
authors.initials: E
authors.lastname: Holland
authors.forename: Bi-Sen
authors.initials: BS
authors.lastname: Ding
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Greenfield
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005910:Glioma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2