Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8388
A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma
Huang, Yujie | Rajappa, Prajwal | Hu, Wenhuo | Hoffman, Caitlin | Cisse, Babacar | Kim, Joon-Hyung | Gorge, Emilie | Yanowitch, Rachel | Cope, William | Vartanian, Emma | Xu, Raymond | Zhang, Tuo | Pisapia, David | Xiang, Jenny | Huse, Jason | Matei, Irina | Peinado Selgas, Hector CNIO | Bromberg, Jacqueline | Holland, Eric | Ding, Bi-Sen | Rafii, Shahin | Lyden, David | Greenfield, Jeffrey
J Clin Invest. 2017 ;127(5):1826-1838.
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.
Animals | Cell Line, Tumor | Granulocyte-Macrophage Colony-Stimulating Factor | Humans | Inhibitor of Differentiation Protein 2 | Mice | Mice, Transgenic | Neoplasm Proteins | Signal Transduction | Transforming Growth Factor beta | Vascular Endothelial Growth Factor Receptor-2 | Bone Marrow Cells | Glioma | Myeloid Cells | Neovascularization, Pathologic