Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect

Abstract

The form and function of blood vessels are determined by the cells that constitute their microenvironment. Brain tissue around tumors contains varying numbers of tumor cells that could influence local capillaries to lose their blood-brain barrier (BBB), as they do in the tumor itself. Microvascular permeability cannot be measured directly in humans but can be inferred from a knowledge of vessel ultrastructure. The authors have examined the vascular ultrastructure associated with the BBB in human peritumoral brain tissue for evidence of BBB compromise and to correlate BBB features with the cellular components of the vessel microenvironment. Light microscopic examination of brain tissue samples in patients with primary brain tumors showed that the tissue lying beyond the visible edge of the tumor ranged from essentially normal to grossly infiltrated with tumor cells. Although some of the vessels were structurally normal, the microvessels as a group had elongated junctional clefts (unfused regions) and an increase in the density of endothelial vesicles. Furthermore, the cleft index (the percentage of the junctional profile that is unfused) varied directly with the local cell density. A subpopulation of vessels enveloped by a layer of tumor cells was grossly abnormal. However, vessels that were not immediately invested by tumor cells also showed some abnormalities. It is concluded that tumor cells infiltrating peritumoral brain tissue cause blood vessels to take on some of the structural characteristics of leaky vessels. Since direct contact is not required, and since the degree of abnormality correlates with the number of tumor cells in the environment, the authors suggest that this inductive influence is exerted over a distance and is dependent on the concentration of the inducing factors.