Astrocytoma and glioblastoma IDH1-wildtype cells colonize tumor vessels and deploy vascular mimicry

ABSTRACT

Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published; however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18 isocitrate dehydrogenase-wildtype (IDH1-wt) glioblastomas and 12 isocitrate dehydrogenase-mutant (IDH1-mt) High-grade gliomas indicated that tumor vessels of both types had undergone deformities such as the thickening of the vessel wall (VW) and proliferation of the basement membrane, contour distortions, abnormal and discontinuous basal lamina, tumor cells’ invasion and colonization of VW, disappearance of endothelial cells (ECs), pericytes, and smooth muscle cells, as well as the formation of a continuous ring of tumor cells attached to the luminal side of VW in numerous cases. The latter feature is a clear sign of vascular mimicry (VM) that was previously suggested in gliomas but never shown by TEM. Additionally, the vascular invasion was carried out by a large number of tumor cells and was accompanied by the accumulation of tumor lipids in the vessels’ lumina and VWs; these two features are distinct for gliomas and may alter the course of the clinical presentation and overall prognosis. This raises the issue of how to specifically target tumor cells involved in vascular invasion in order to optimize prognosis and overcome these mechanisms employed by the tumor cells.

KEYWORDS:

• Basal lamina
• basement membrane
• endothelial cells
• glioma
• pericyte
• smooth muscle cell
• vessel wall

Disclosure statement

No potential conflict of interest was reported by the authors.

Authorship

Conception and design of the study/experiments: MAA, OA

Experimental implementation/Data acquisition: MAA

Data analysis and interpretation: HM, MAA, OA

Drafting of manuscript: HM, MAA, HSL, OA

Revision of the manuscript and approval of final version: HM, MAA, HSL, OA

All listed authors participated in the writing of the manuscript and have read and approved the final version.

Abbreviations

Endothelial cell = EC; isocitrate dehydrogenase = IDH; IDH-mutant = IDH-mt; IDH1-wildtype = IDH1-wt; vascular mimicry = VM; vascular wall = VW.

Additional information

Funding

Dr. Aboud is supported in part by the UC Davis Paul Calabresi Career Development Award for Clinical Oncology as funded by the National Cancer Institute, National Institutes of Health through grant #2K12CA138464-11. Dr. Abu-Asab is supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health.