期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 5, 页码 1826-1838出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI86443
关键词
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资金
- Department of Defense Congressionally Directed Medical Research Programs (DOD CDMRP) [CA120318]
- Elizabeth's Hope
- Starr Foundation
- Paduano Foundation
- Champalimaud Foundation
- Malcolm Hewitt Wiener Foundation
- POETIC Foundation
- Sohn Foundation
- Hartwell Foundation
- Children's Cancer and Blood Foundation
- CDMRP [CA120318, 542411] Funding Source: Federal RePORTER
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-beta 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.
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