A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.

TitleA proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma.
Publication TypeJournal Article
Year of Publication2017
AuthorsHuang Y, Rajappa P, Hu W, Hoffman C, Cisse B, Kim J-H, Gorge E, Yanowitch R, Cope W, Vartanian E, Xu R, Zhang T, Pisapia D, Xiang J, Huse J, Matei I, Peinado H, Bromberg J, Holland E, Ding B-S, Rafii S, Lyden D, Greenfield J
JournalJ Clin Invest
Date Published2017 May 01
KeywordsAnimals, Bone Marrow Cells, Cell Line, Tumor, Glioma, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Inhibitor of Differentiation Protein 2, Mice, Mice, Transgenic, Myeloid Cells, Neoplasm Proteins, Neovascularization, Pathologic, Signal Transduction, Transforming Growth Factor beta, Vascular Endothelial Growth Factor Receptor-2

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.

Alternate JournalJ Clin Invest
PubMed ID28394259
PubMed Central IDPMC5409793
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States