| Abstrakt: |
Blood vessels of tumors have multiple cellular abnormalities that impair blood flow and drug delivery but provide targets for novel therapeutics. These abnormalities involve all components of the vessel wall, including endothelial cells, pericytes, and vascular basement membrane. Endothelial cells of tumor vessels have abnormal gene expression, are dynamic, and undergo sprouting, proliferation, and regression. The endothelial cells have a defective barrier function, are leaky, and may depend on vascular endothelial growth factor (VEGF) for survival. Pericytes of tumor vessels lack the normally intimate association with endothelial cells, and the surrounding basement membrane has redundant loose layers that reflect continual remodeling of the vasculature. Studies of the cellular actions of VEGF inhibitors on mouse models of spontaneous and implanted tumors have shown rapid, robust changes in tumor vessels. Strikingly, in some tumors, within 24 h, endothelial fenestrations disappear, vascular sprouting is suppressed, blood flow ceases, and patency is lost in many vessels. As many as 80% of tumor vessels may regress within 7 days. Similarly, normal blood vessels with abundant endothelial fenestrations, as in the gastrointestinal tract, kidney, and endocrine organs, may be sensitive to VEGF inhibitors. Surviving tumor vessels acquire more normal features, including uniform caliber, diminished branching, reduced VEGFR-2 expression, and tighter pericyte coverage. Empty sleeves ofvascularbasementmembrane, leftbehind after endothelial cells degenerate, provide a record of pretreatment vessel number and a scaffold for vascular regrowth after cessation of therapy. Normalization of surviving tumor vessels may improve local hemodynamics and perivascular delivery of oxygen, nutrients, and therapeutics, despite reduced angiogenesis and tumor vascularity. [ABSTRACT FROM AUTHOR] |
