Pro-angiogenic vascular stem cells and angiogenesis are key events in the process of glioma formation. Vascular lesions that arise from a focal budding of endothelial cells have been associated with a poor prognosis in glioblastoma multiforme. Hyper-proliferative endothelial lesions are common in patients with severe brain tumors, however, little is known about the relevance of vascular stem cells in the development of these lesions. We tested the hypothesis that the overexpression of the inhibitor of DNA binding and differentiation protein 3 (ID3) reprograms the molecular signature of endothelial cells to stem-like cells; and we hypothesize that these stem-like cells participate in the development of vascular lesion formation in glioma. We generated ID3 overexpressing cells using the human cerebral microvascular endothelial cell line, hCMEC/D3; and determined the effect of ID3 on molecular stem-like signature and vascular lesion formation. ID3 overexpressing cells resided more in the G0/G1 phase and showed a significantly higher level of stem cell markers CD34, CD133, Oct-4, and Sox-2 than wild-type cells. ID3 overexpressing cells also showed a significant increase in VEGFR3, an endothelial growth factor receptor that has been previously reported to correlate with tumor grade of malignant gliomas. In addition, ID3 overexpressing cells showed increased levels of Pyk2, a kinase that has been shown to control glioma cell migration. In the 3-D culture model, we observed that ID3 was essential for the growth of endothelial spheroids. Our findings demonstrate that ID3 generated vascular stem-like cells have the capacity to participate in vascular lesion formation and that vascular stem-like molecular signatures are regulated in part by ID3. Furthermore, the correlation of ID3 overexpression with an increase in VEGFR3 and Pyk2 suggests the importance of ID3 in malignant glioma endothelium. Assessing ID3 in malignant gliomas on a functional level may enable a better understanding for how the microvascular niche contributes to the development of glioma. A better understanding of how microvascular lesions depend on ID3 may open new avenues for the prevention and treatment of glioma.

Citation Format: Jayanta Das, Quentin H. Felty. Id3 generated cancer stem-like cells: A microvascular niche for the development of glioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4179. doi:10.1158/1538-7445.AM2015-4179