Os Are the Major Site of Hyperpermeability of Tumor Blood Vessels

Tumor microvessels are typically fourfold to tenfold more permeable to circulating macromolecules than comparable normal vessels. We injected several different macro-molecular tracers intravenously into mice or guinea pigs bearing solid or ascites tumors and followed the extravasation of these tracers from tumor and normal vessels over time by light and electron microscopy [1, 2]. These studies led to the identification of VVOs in the endothelium of tumor microvessels. The vesicles and vacuoles of individual VVOs extend across endothelial cells, interconnecting with each other and with the luminal, abluminal, and often the lateral plasma membranes by stomata that may be open or that are guarded by thin diaphragms. These stomata and their closing diaphragms likely provide the structural basis for regulation of tracer passage across the microvascular endothelium.

VVOs were found to provide a transcytotic pathway by which soluble macromolecular tracers extravasated from leaky tumor blood vessels. Within seconds of intravenous

Figure 1 Platelet endothelial cell adhesion molecule (PECAM, CD31) localization to a VVO and plasma membranes (luminal and abluminal) of a mouse skin venule. In this thickened portion of venular endothelium the characteristic VVO stretches from the luminal to the abluminal surfaces of this endothelial cell. Localization is with an immunonanogold method. Particles are associated with stomata and their diaphragms (arrow), which typify the ultrastructural anatomy of VVOs. L, Lumen. Bar = 170 nm.

Figure 1 Platelet endothelial cell adhesion molecule (PECAM, CD31) localization to a VVO and plasma membranes (luminal and abluminal) of a mouse skin venule. In this thickened portion of venular endothelium the characteristic VVO stretches from the luminal to the abluminal surfaces of this endothelial cell. Localization is with an immunonanogold method. Particles are associated with stomata and their diaphragms (arrow), which typify the ultrastructural anatomy of VVOs. L, Lumen. Bar = 170 nm.

injection into tumor-bearing mice, macromolecular tracers were found in VVO vesicles that opened to the vascular lumen. Initially, tracers were found in VVO vesicles that opened to the vascular lumen, but VVO vesicles and vacuoles were rapidly labeled at all levels of endothelial cell cytoplasm. Vesicles that opened to the endothelial cell ablumen spilled both tracers into the underlying basal lamina. Ferritin (d ~ 11 nm) was not found to exit tumor vessels through interendothelial cell junctions at any time interval up to 1 hour. The small protein tracer HRP (d ~ 5 nm) did exit tumor vessels through normally apposed interendothelial junctions, but only after a delay of at least 5 minutes, at a time when extensive HRP extravasation had already taken place through VVOs.

Subsequent study revealed that morphologically similar VVOs were present, and with equal frequency, in the venu-lar endothelium supplying skin and many other tissues in normal animals as well as remote from tumor sites in tumor-bearing animals. However, normal venules extravasated only very small amounts of macromolecules and their VVOs were minimally labeled with ferritin and HRP.

Vessels supplying some tumors were fenestrated and prominent collections of ferritin were also found in and beneath individual fenestrae, suggesting that these structures had provided a second pathway for tracer extravasation [1]. In contrast, some vessels supplying other tumors were not fenestrated, and tracer extravasated exclusively by the transcellular VVO route.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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