Tumor vessels are structurally and functionally abnormal. In contrast to normal vessels, tumor vasculature is highly disorganized, e.g., vessels are tortuous and dilated, with uneven diameters, excessive branching, and numerous openings. This may be due to an imbalance of angiogenic regulators, such as VEGF and angiopoi-etins (Carmeliet and Jain 2000). They may lack functional perivascular cells, which are needed to protect vessels against changes in oxygen or hormonal balance, provide them necessary vasoactive control to accommodate metabolic needs, and induce vascular quiescence. As the result, tumor blood flow is chaotic and variable
(Baish and Jain 2000). Due to the irregular and chaotic structure of the vascular system in tumors, some areas do not obtain enough blood supply and become oxygen starved (hypoxic) (Helmlinger et al. 1997). These areas also become acidic as hypoxic tumors cannot adequately remove waste through the blood stream. The hypoxic tumor cells are difficult to treat if the anticancer drugs are to be delivered through the blood stream. Radiation treatments which create oxygen radicals that attack the DNA of tumor cell are also ineffective to kill these tumor cells.
Tumorous tissues not only have higher vascular density compared to normal tissues but the structure of tumor vessels is also abnormal: the walls of tumor vessels have numerous "openings" (such as endothelial fenestrate, vesicles, and transcel-lular holes), widened interendothelial junctions, and a discontinuous or absent basement membrane. The endothelial cells are also abnormal in shape, growing on top of each other and projecting into the lumen. Tumor vessels, therefore, are leakier than those of healthy, normal tissues (Carmeliet and Jain 2000). Rapid vascularization also leads to impaired lymphatic drainage systems in tumor tissue. The high vascular density of tumors, their leaky vessels, and defective or suppressed lymphatic drainage in the tumor interstitium comprise the so-called "enhanced permeation and retention (EPR)" effects which anticancer treatment methods can take advantage of (Sledge and Miller 2003; Teicher 2000).
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