A proangiogenic signaling axis in myeloid cells promotes malignant progression of glioma Journal Article
| Authors: | Huang, 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. |
| Article 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. |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 127 |
| Issue: | 5 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2017-05-01 |
| Start Page: | 1826 |
| End Page: | 1838 |
| Language: | English |
| DOI: | 10.1172/jci86443 |
| PROVIDER: | scopus |
| PMCID: | PMC5409793 |
| PUBMED: | 28394259 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2017 -- Source: Scopus |
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