The capillary endothelium within brain tumors has sometimes been called the ''blood-brain tumor barrier'' [2,33]. Clinically, the permeability of this endothelium (and degree of vascularity) is indicated by the degree of tumor enhancement on CT and/or MRI scans. Meningiomas and brain metastases, as examples, would not be expected to have a true BBB, at least by the time they are visible by current neuroimaging studies. Most of the blood supply of meningiomas is derived from the dura; neither meningiomas nor metastases contain the astrocytes needed for the induction of the BBB during neovascularization. The structure of capillaries in malignant gliomas has been studied using light and electron microscopy [2,7,14,15,42]. Such studies have indicated that tumor capillaries are often surrounded by large collagen-filled extracellular spaces with gaps in the basal lamina and absent glial processes [2,42]; changes that are consistent with passage of large molecules across the endothelium. Molecular changes, such as alterations in claudins and occludin, have also been demonstrated .
Quantitative measurements of brain tumor capillary permeability in animal brain tumor models and human gliomas have indicated that capillary permeability in gliomas is regionally variable, and can be 10-30 times that of normal brain . For gliomas and micrometastases, the real issue relates to the permeability of the endothelium in the region adjacent to, or even distant from, what is clearly demarcated as tumor by current imaging techniques. The enhancing (central) portion of a tumor can be addressed by techniques aimed at local control, such as surgery or radiosurgery. Unfortunately, malignant cells migrate into (or metastasize to) deeper brain regions where the BBB is at least initially intact, and thus may be shielded from the action of chemotherapeutic agents. Sometimes it has been assumed that the capillary permeability (and thus drug penetration) of the brain adjacent to tumor (BAT) is simply intermediate between that of the area of greatest BBB disruption, and that of normal brain. Such assumptions may not be accurate enough to plan therapy in a rational and successful manner. Better data pertaining to the delivery of specific drugs to brain tumors and the brain in individual patients is needed.
Brain tumor growth is often associated with BBB disruption and the development of tumor-associated (vasogenic) edema. Such edema has deleterious effects on cerebral blood flow, brain metabolism and intracranial pressure [2,7,42]. A variety of in vitro and animal models (C6, 9L, RG-2, and others) have been used to study the effects of brain tumor cells on the BBB, and the resultant edema formation [2,37]. Theoretically, tumor cells could affect BBB permeability in at least two ways:
(1) directly, through invasion or mechanical interference, and/or
(2) indirectly, by the production of diffusible molecules (''permeability factors'') able to act at a distance from tumor cells [2,7].
In addition, glioma cells, unlike normal brain glia, probably lack the ability to induce the formation of a normal BBB. Mechanically, it has long been known that glioma cells often infiltrate brain parenchyma along ''paths of least resistance'' e.g. ''Virchow-Robin'' spaces and/or myelinated fiber tracts . Proliferation of tumor cells adjacent to small vessels could directly affect capillary integrity and function [2,7]. It is likely that ''a critical threshold'' (in terms—as examples—of a percentage of brain tissue occupied by tumor cells, or the amount of ''permeability factor'' present) may need to be reached, before BBB disruption is detected, as illustrated in Fig. 16.2.
Observations regarding capillaries in brain tissue adjacent to tumors help explain the basis for BBB disruption. Studies have shown an increase in open junctions and pinocytoic vesicles in BAT capillaries, arguing for the importance of diffusible factors in the pathogenesis of BBB disruption [2,7,42]. Several BBB ''permeability factors'' have been identified for brain tumors. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and has extremely potent effects on microvascular permeability . VEGF is expressed in malignant gliomas and its receptor is upregulated in tumor endothelial cells . Degradation products of cell membrane phospho-lipids may also act as permeability factors, and be associated with changes in phospholipase A2 activity, arachidonic acid release, and increased production of leukotrienes and/or prostaglandins. Prostaglandin E and thromboxane B2 also act as vascular permeability factors [2,42]. Much research has focused on identifying proteolytic enzymes secreted by gliomas, which include:
(1) urokinase, a serine protease which is a plasmino-gen activator;
(2) matrix metalloproteinases, which include type IV and other collagenases, gelatinases and stro-melysins, and
figure 16.2 MRI scans illustrating the critical threshold concept for BBB disruption. Left: Gadolinium-enhanced MRI of a glioblastoma patient prior to tumor recurrence. Right: Similar slice, 12 weeks later. It is likely that tumor cells were radially distributed around the area of the occipital horn at the time of the scan at the left, but had not yet achieved the required density for BBB disruption, and thus detected by MRI.
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