1 research outputs found
A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma
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.This study was supported by the Department of Defense Con-
gressionally Directed Medical Research Programs (DOD CDMRP,
CA120318 to Y. Huang), Elizabeth’s Hope (J. Greenfield), the Starr
Foundation, the Paduano Foundation, the Champalimaud Foun-
dation, the Malcolm Hewitt Wiener Foundation, the POETIC
Foundation, the Sohn Foundation, the Hartwell Foundation, and
the Children’s Cancer and Blood Foundation (all to D. Lyden).
Address correspondence to: David Lyden, Department of
Pediatrics, Weill Medical Medicine, 413 E. 69th Street, Box
284, New York, New York 10021, USA. Phone: 646.962.6238;
E-mail: [email protected]. Or to: Jeffrey P. Greenfield,
Department of Neurological Surgery, Weill Cornell Medicine,
525 E 68th Street, Box 99, New York, New York 10065, USA.
Phone: 212.746.2363; E-mail: [email protected].
HP’s present address is: Microenvironment and Metastasis
Group, Department of Molecular Oncology, Spanish National
Cancer Research Center (CNIO), Madrid, Spain.S